[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"_public_publisher_byId_399e3fd6-cddd-4e8b-8b15-22cd72b4823e":3,"_public_publication_all{\"sortAscending\":false,\"sortField\":\"updateTime\",\"page\":0,\"size\":10,\"facet\":true,\"searchKey\":\"publisherId:399e3fd6-cddd-4e8b-8b15-22cd72b4823e,\"}":23},{"code":4,"data":5,"meta":18},"SUCCESS",{"id":6,"createTime":7,"updateTime":8,"relativeEntities":9,"slug":10,"properties":11,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":20,"manageAffiliations":21,"indexDatabases":22,"url":18,"thumbnailPath":18,"statistic":18,"gsStatistic":18,"type":18,"analyzePriority":18},"399e3fd6-cddd-4e8b-8b15-22cd72b4823e","2024-12-04T14:34:10.190+00:00","2025-02-09T08:14:31.245+00:00",[],"American-Association-for-Cancer-Research-AACR-",{"eissn":12,"title":14},{"VOID":13},"1538-7445",{"EN":15},"American Association for Cancer Research (AACR)","PUBLISHER","PENDING",null,0,[],[],[],{"meta":24,"data":26},{"total":25},"75",[27,345,750,1118,1390,1783,2129,2850,3191,3496],{"id":28,"createTime":29,"updateTime":29,"relativeEntities":30,"slug":31,"properties":32,"entityType":46,"verifyStatus":47,"verifyTime":48,"verifyNote":49,"syncStatus":17,"languages":50,"translateLanguages":18,"viewCount":19,"primaryUrl":52,"fullTextUrl":18,"authors":53,"publicationType":111,"publisherRelationship":112,"citationCount":128,"citationInfo":129,"publishDate":139,"publishYear":140,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":141,"isForceReanalyzing":344},"06d5ea47-ce4f-42ca-8173-40697a66a7df","2024-12-24T22:58:19.687+00:00",[],"Suppression-of-Human-Solid-Tumor-Growth-in-Mice-by-Intratumor-and-Systemic-Inoculation-of-Histidine-Rich-and-pH-Dependent-Host-Defense-like-Lytic-Peptides",{"mag":33,"keywords":35,"openalex":36,"abstract":38,"title":40,"pm":42,"doi":44},{"VOID":34},"2057443193",{},{"VOID":37},"W2057443193",{"EN":39},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>Previously, we reported that intratumor or systemic inoculation of a cationic 15-mer, innate immunity-like lytic peptide composed of d- and l-amino acids ([D]-K6L9) caused growth arrest of 22RV1 prostate carcinoma xenografts in a mouse model. However, despite its therapeutic potential, this peptide has significant systemic toxicity at concentrations slightly higher than the therapeutic one. Here, we used the acidic environment created by solid tumors as a trigger to activate anticancer lytic peptides by making them cationic only at low pH levels. We achieved this selectivity by substituting lysines (pKa, ∼10.5) for histidines (pKa, ∼6.1) in the parental peptide [D]-K6L9. Histidine is protonated below pH 7. For that purpose, we replaced either three or all six lysines in the parental peptide with histidines to obtain the peptides [D]-K3H3L9 and [D]-H6L9. Interestingly, in vitro experiments showed pH-dependent activity only with [D]-H6L9 mainly toward cancer cell lines. However, both peptides showed reduced systemic toxicity compared with the parental peptide. Intratumor and systemic inoculation of these peptides resulted in a significant decrease in the 22RV1 prostate cancer tumor volume and systemic secretion of prostate-specific antigen in a xenograft mice model. Moreover, histologic modifications revealed a significant reduction in new blood vessels selectively in tumor tissues after treatment with the peptides compared with the untreated tumors. The lytic mode of action of these new peptides, which makes it difficult for the cancer cells to develop resistance, and their selective and pH-dependent activity make them potential candidates for treatment of solid cancer tumors. [Cancer Res 2009;69(8):3458–63]\u003C\u002Fjats:p>",{"EN":41},"Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides",{"VOID":43},"19351852",{"VOID":45},"10.1158\u002F0008-5472.can-08-3021","PUBLICATION","VERIFIED","2024-12-24T22:58:19.686+00:00","Auto Verify",[51],"EN","https:\u002F\u002Faacrjournals.org\u002Fcancerres\u002Farticle\u002F69\u002F8\u002F3458\u002F553309\u002FSuppression-of-Human-Solid-Tumor-Growth-in-Mice-by",[54,78,95],{"id":55,"sortIndex":56,"researcher":18,"roles":57,"affiliations":58,"properties":71},"72a022a8-6970-4bca-ba3f-f0ad281cdaaa",2,[],[59],{"id":60,"sortIndex":19,"affiliation":61,"properties":18},"d8c3803c-f9f6-48fa-974b-e4eca6205050",{"id":62,"createTime":63,"updateTime":64,"relativeEntities":65,"slug":66,"properties":67,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"16bb99c4-bb70-4369-8ad2-a854dcf409fb","2024-01-21T14:49:39.362+00:00","2024-12-24T22:58:19.706+00:00",[],"Department-of-Biological-Chemistry-The-Weizmann-Institute-of-Science-Rehovot-Israel",{"title":68},{"VI":69},"Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel","AFFILIATION",{"openalex":72,"orcid":74,"title":76},{"VOID":73},"A5103195244",{"VOID":75},"https:\u002F\u002Forcid.org\u002F0000-0002-8588-5586",{"EN":77},"Yechiel Shai",{"id":79,"sortIndex":19,"researcher":18,"roles":80,"affiliations":81,"properties":88},"831e2d4d-769f-4619-abcd-d0509f48713f",[],[82],{"id":83,"sortIndex":19,"affiliation":84,"properties":18},"dcfa69f8-e285-4249-9da7-8a739bf47d9c",{"id":62,"createTime":63,"updateTime":64,"relativeEntities":85,"slug":66,"properties":86,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":87},{"VI":69},{"openalex":89,"orcid":91,"title":93},{"VOID":90},"A5014755225",{"VOID":92},"https:\u002F\u002Forcid.org\u002F0000-0003-4274-2224",{"EN":94},"Arik Makovitzki",{"id":96,"sortIndex":97,"researcher":18,"roles":98,"affiliations":99,"properties":106},"99b09509-c92f-41ab-a375-4e940d9fa215",1,[],[100],{"id":101,"sortIndex":19,"affiliation":102,"properties":18},"7566cfab-a6db-4869-b6e3-c688557b9e92",{"id":62,"createTime":63,"updateTime":64,"relativeEntities":103,"slug":66,"properties":104,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":105},{"VI":69},{"openalex":107,"title":109},{"VOID":108},"A5074405828",{"EN":110},"Avner Fink","ARTICLE",{"url":18,"publisher":113,"properties":121},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":114,"slug":10,"properties":115,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":118,"manageAffiliations":119,"indexDatabases":120,"url":18,"thumbnailPath":18,"statistic":18,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"eissn":116,"title":117},{"VOID":13},{"EN":15},[],[],[],{"volume":122,"pages":124,"issue":126},{"VOID":123},"69",{"VOID":125},"3458-3463",{"VOID":127},"8",98,{"total":128,"publishYear":18,"statisticByYear":130},{"2012":131,"2013":132,"2014":133,"2015":134,"2016":134,"2017":97,"2018":135,"2019":136,"2020":136,"2021":131,"2022":137,"2023":138,"2024":136},5,15,9,4,3,6,8,7,"2009-04-15",2009,[142,145,149,152,155,158,162,166,170,174,178,182,186,190,194,198,202,206,210,214,218,222,226,230,234,238,242,246,250,254,258,262,265,269,273,277,281,285,289,293,297,301,305,309,313,317,321,325,329,333,337,340],{"id":18,"text":143,"url":18,"identifiers":144},"Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989; 49: 6449–65.",{},{"id":18,"text":146,"url":18,"identifiers":147},"Pan JG, Mak TW. Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007; 2007: p14.",{"doi":148},"10.1126\u002Fstke.3812007pe14",{"id":18,"text":150,"url":18,"identifiers":151},"Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989; 49: 4373–84.",{},{"id":18,"text":153,"url":18,"identifiers":154},"Jahde E, Rajewsky MF, Baumgartl H. pH distributions in transplanted neural tumors and normal tissues of BDIX rats as measured with pH microelectrodes. Cancer Res 1982; 42: 1498–504.",{},{"id":18,"text":156,"url":18,"identifiers":157},"Martin GR, Jain RK. Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res 1994; 54: 5670–4.",{},{"id":18,"text":159,"url":18,"identifiers":160},"Newell K, Franchi A, Pouyssegur J, Tannock I. Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci U S A 1993; 90: 1127–31.",{"doi":161},"10.1073\u002Fpnas.90.3.1127",{"id":18,"text":163,"url":18,"identifiers":164},"Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984; 2: 343–66.",{"doi":165},"10.1016\u002FS0167-8140(84)80077-8",{"id":18,"text":167,"url":18,"identifiers":168},"Zhao R, Gao F, Hanscom M, Goldman ID. A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier. Clin Cancer Res 2004; 10: 718–27.",{"doi":169},"10.1158\u002F1078-0432.CCR-1066-03",{"id":18,"text":171,"url":18,"identifiers":172},"Wang Y, Zhao R, Goldman ID. Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier. Clin Cancer Res 2004; 10: 6256–64.",{"doi":173},"10.1158\u002F1078-0432.CCR-04-0645",{"id":18,"text":175,"url":18,"identifiers":176},"Park HJ, Lyons JC, Ohtsubo T, Song CW. Acidic environment causes apoptosis by increasing caspase activity. Br J Cancer 1999; 80: 1892–7.",{"doi":177},"10.1038\u002Fsj.bjc.6690617",{"id":18,"text":179,"url":18,"identifiers":180},"Reshetnyak YK, Andreev OA, Lehnert U, Engelman DM. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proc Natl Acad Sci U S A 2006; 103: 6460–5.",{"doi":181},"10.1073\u002Fpnas.0601463103",{"id":18,"text":183,"url":18,"identifiers":184},"Lee ES, Na K, Bae YH. Super pH-sensitive multifunctional polymeric micelle. Nano Lett 2005; 5: 325–9.",{"doi":185},"10.1021\u002Fnl0479987",{"id":18,"text":187,"url":18,"identifiers":188},"Ko J, Park K, Kim YS, et al. Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy. J Control Release 2007; 123: 109–15.",{"doi":189},"10.1016\u002Fj.jconrel.2007.07.012",{"id":18,"text":191,"url":18,"identifiers":192},"Lee ES, Na K, Bae YH. Polymeric micelle for tumor pH and folate-mediated targeting. J Control Release 2003; 91: 103–13.",{"doi":193},"10.1016\u002FS0168-3659(03)00239-6",{"id":18,"text":195,"url":18,"identifiers":196},"Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002; 415: 389–95.",{"doi":197},"10.1038\u002F415389a",{"id":18,"text":199,"url":18,"identifiers":200},"Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 2006; 24: 1551–7.",{"doi":201},"10.1038\u002Fnbt1267",{"id":18,"text":203,"url":18,"identifiers":204},"Mader JS, Hoskin DW. Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin Investig Drugs 2006; 15: 933–46.",{"doi":205},"10.1517\u002F13543784.15.8.933",{"id":18,"text":207,"url":18,"identifiers":208},"Lehmann J, Retz M, Sidhu SS, et al. Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines. Eur Urol 2006; 50: 141–7.",{"doi":209},"10.1016\u002Fj.eururo.2005.12.043",{"id":18,"text":211,"url":18,"identifiers":212},"Meyer JE, Harder J. Antimicrobial peptides in oral cancer. Curr Pharm Des 2007; 13: 3119–30.",{"doi":213},"10.2174\u002F138161207782110372",{"id":18,"text":215,"url":18,"identifiers":216},"Hoskin DW, Ramamoorthy A. Studies on anticancer activities of antimicrobial peptides. Biochim Biophys Acta 2008; 1778: 357–75.",{"doi":217},"10.1016\u002Fj.bbamem.2007.11.008",{"id":18,"text":219,"url":18,"identifiers":220},"Papo N, Shai Y. Host defense peptides as new weapons in cancer treatment. Cell Mol Life Sci 2005; 62: 784–90.",{"doi":221},"10.1007\u002Fs00018-005-4560-2",{"id":18,"text":223,"url":18,"identifiers":224},"Papo N, Braunstein A, Eshhar Z, Shai Y. Suppression of human prostate tumor growth in mice by a cytolytic d-, l-amino acid peptide: membrane lysis, increased necrosis, and inhibition of prostate-specific antigen secretion. Cancer Res 2004; 64: 5779–86.",{"doi":225},"10.1158\u002F0008-5472.CAN-04-1438",{"id":18,"text":227,"url":18,"identifiers":228},"Papo N, Seger D, Makovitzki A, et al. Inhibition of tumor growth and elimination of multiple metastases in human prostate and breast xenografts by systemic inoculation of a host defense-like lytic peptide. Cancer Res 2006; 66: 5371–8.",{"doi":229},"10.1158\u002F0008-5472.CAN-05-4569",{"id":18,"text":231,"url":18,"identifiers":232},"Patel BJ, Pantuck AJ, Zisman A, et al. CL1-GFP: an androgen independent metastatic tumor model for prostate cancer. J Urol 2000; 164: 1420–5.",{"doi":233},"10.1016\u002FS0022-5347(05)67210-2",{"id":18,"text":235,"url":18,"identifiers":236},"Sramkoski RM, Pretlow TG II, Giaconia JM, et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim 1999; 35: 403–9.",{"doi":237},"10.1007\u002Fs11626-999-0115-4",{"id":18,"text":239,"url":18,"identifiers":240},"Allen TM, Cleland LG. Serum-induced leakage of liposome contents. Biochim Biophys Acta 1980; 597: 418–26.",{"doi":241},"10.1016\u002F0005-2736(80)90118-2",{"id":18,"text":243,"url":18,"identifiers":244},"Gavish Z, Pinthus JH, Barak V, et al. Growth inhibition of prostate cancer xenografts by halofuginone. Prostate 2002; 51: 73–83.",{"doi":245},"10.1002\u002Fpros.10059",{"id":18,"text":247,"url":18,"identifiers":248},"Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 1997; 89: 1121–32.",{"doi":249},"10.1182\u002Fblood.V89.4.1121",{"id":18,"text":251,"url":18,"identifiers":252},"Papo N, Shai Y. New lytic peptides based on the d, l amphipathic helix motif preferentially kill tumor cells compared with normal cells. Biochemistry 2003; 42: 9346–54.",{"doi":253},"10.1021\u002Fbi027212o",{"id":18,"text":255,"url":18,"identifiers":256},"Zachowski A. Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J 1993; 294: 1–14.",{"doi":257},"10.1042\u002Fbj2940001",{"id":18,"text":259,"url":18,"identifiers":260},"Dennison SR, Whittaker M, Harris F, Phoenix DA. Anticancer α-helical peptides and structure\u002Ffunction relationships underpinning their interactions with tumour cell membranes. Curr Protein Pept Sci 2006; 7: 487–99.",{"doi":261},"10.2174\u002F138920306779025611",{"id":18,"text":263,"url":18,"identifiers":264},"Utsugi T, Schroit AJ, Connor J, Bucana CD, Fidler IJ. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res 1991; 51: 3062–6.",{},{"id":18,"text":266,"url":18,"identifiers":267},"Dobrzynska I, Szachowicz-Petelska B, Sulkowski S, Figaszewski Z. Changes in electric charge and phospholipids composition in human colorectal cancer cells. Mol Cell Biochem 2005; 276: 113–9.",{"doi":268},"10.1007\u002Fs11010-005-3557-3",{"id":18,"text":270,"url":18,"identifiers":271},"Cappelli G, Paladini S, D'Agata A. [Tumor markers in the diagnosis of pancreatic cancer]. Tumori 1999; 85: S19–21.",{"doi":272},"10.1177\u002F030089169908501s06",{"id":18,"text":274,"url":18,"identifiers":275},"Burdick MD, Harris A, Reid CJ, Iwamura T, Hollingsworth MA. Oligosaccharides expressed on MUC1 produced by pancreatic and colon tumor cell lines. J Biol Chem 1997; 272: 24198–202.",{"doi":276},"10.1074\u002Fjbc.272.39.24198",{"id":18,"text":278,"url":18,"identifiers":279},"Kichler A, Leborgne C, Marz J, Danos O, Bechinger B. Histidine-rich amphipathic peptide antibiotics promote efficient delivery of DNA into mammalian cells. Proc Natl Acad Sci U S A 2003; 100: 1564–8.",{"doi":280},"10.1073\u002Fpnas.0337677100",{"id":18,"text":282,"url":18,"identifiers":283},"van Kan EJ, van der Bent A, Demel RA, de Kruijff B. Membrane activity of the peptide antibiotic clavanin and the importance of its glycine residues. Biochemistry 2001; 40: 6398–405.",{"doi":284},"10.1021\u002Fbi0028136",{"id":18,"text":286,"url":18,"identifiers":287},"Czajkowsky DM, Iwamoto H, Cover TL, Shao Z. The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc Natl Acad Sci U S A 1999; 96: 2001–6.",{"doi":288},"10.1073\u002Fpnas.96.5.2001",{"id":18,"text":290,"url":18,"identifiers":291},"Lai R, Takeuchi H, Lomas LO, et al. A new type of antimicrobial protein with multiple histidines from the hard tick, Amblyomma hebraeum. FASEB J 2004; 18: 1447–9.",{"doi":292},"10.1096\u002Ffj.03-1154fje",{"id":18,"text":294,"url":18,"identifiers":295},"Kacprzyk L, Rydengard V, Morgelin M, et al. Antimicrobial activity of histidine-rich peptides is dependent on acidic conditions. Biochim Biophys Acta 2007; 1768: 2667–80.",{"doi":296},"10.1016\u002Fj.bbamem.2007.06.020",{"id":18,"text":298,"url":18,"identifiers":299},"van Kan EJ, Demel RA, van der Bent A, de Kruijff B. The role of the abundant phenylalanines in the mode of action of the antimicrobial peptide clavanin. Biochim Biophys Acta 2003; 1615: 84–92.",{"doi":300},"10.1016\u002FS0005-2736(03)00233-5",{"id":18,"text":302,"url":18,"identifiers":303},"van Kan EJ, Demel RA, Breukink E, van der Bent A, de Kruijff B. Clavanin permeabilizes target membranes via two distinctly different pH-dependent mechanisms. Biochemistry 2002; 41: 7529–39.",{"doi":304},"10.1021\u002Fbi012162t",{"id":18,"text":306,"url":18,"identifiers":307},"Ringstad L, Kacprzyk L, Schmidtchen A, Malmsten M. Effects of topology, length, and charge on the activity of a kininogen-derived peptide on lipid membranes and bacteria. Biochim Biophys Acta 2007; 1768: 715–27.",{"doi":308},"10.1016\u002Fj.bbamem.2006.11.016",{"id":18,"text":310,"url":18,"identifiers":311},"Lee IH, Cho Y, Lehrer RI. Effects of pH and salinity on the antimicrobial properties of clavanins. Infect Immun 1997; 65: 2898–903.",{"doi":312},"10.1128\u002Fiai.65.7.2898-2903.1997",{"id":18,"text":314,"url":18,"identifiers":315},"van Kraaij C, Breukink E, Noordermeer MA, et al. Pore formation by nisin involves translocation of its C-terminal part across the membrane. Biochemistry 1998; 37: 16033–40.",{"doi":316},"10.1021\u002Fbi980931b",{"id":18,"text":318,"url":18,"identifiers":319},"Makovitzki A, Shai Y. pH-dependent antifungal lipopeptides and their plausible mode of action. Biochemistry 2005; 44: 9775–84.",{"doi":320},"10.1021\u002Fbi0502386",{"id":18,"text":322,"url":18,"identifiers":323},"Vogt TC, Bechinger B. The interactions of histidine-containing amphipathic helical peptide antibiotics with lipid bilayers. The effects of charges and pH. J Biol Chem 1999; 274: 29115–21.",{"doi":324},"10.1074\u002Fjbc.274.41.29115",{"id":18,"text":326,"url":18,"identifiers":327},"Leroux J, Roux E, Le Garrec D, Hong K, Drummond DC. N-isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles. J Control Release 2001; 72: 71–84.",{"doi":328},"10.1016\u002FS0168-3659(01)00263-2",{"id":18,"text":330,"url":18,"identifiers":331},"Kichler A, Mason AJ, Bechinger B. Cationic amphipathic histidine-rich peptides for gene delivery. Biochim Biophys Acta 2006; 1758: 301–7.",{"doi":332},"10.1016\u002Fj.bbamem.2006.02.005",{"id":18,"text":334,"url":18,"identifiers":335},"Boman HG. Peptide antibiotics and their role in innate immunity. Annu Rev Immunol 1995; 13: 61–92.",{"doi":336},"10.1146\u002Fannurev.iy.13.040195.000425",{"id":18,"text":338,"url":18,"identifiers":339},"Ran S, Downes A, Thorpe PE. Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res 2002; 62: 6132–40.",{},{"id":18,"text":341,"url":18,"identifiers":342},"Ran S, Thorpe PE. Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy. Int J Radiat Oncol Biol Phys 2002; 54: 1479–84.",{"doi":343},"10.1016\u002FS0360-3016(02)03928-7",false,{"id":346,"createTime":347,"updateTime":347,"relativeEntities":348,"slug":349,"properties":350,"entityType":46,"verifyStatus":47,"verifyTime":364,"verifyNote":49,"syncStatus":17,"languages":365,"translateLanguages":18,"viewCount":19,"primaryUrl":366,"fullTextUrl":18,"authors":367,"publicationType":111,"publisherRelationship":651,"citationCount":667,"citationInfo":668,"publishDate":670,"publishYear":671,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":672,"isForceReanalyzing":344},"5e35c97e-87fc-429c-9eb4-e84fc4e84147","2024-12-10T22:53:54.093+00:00",[],"A-Recurrent-Chromosome-Breakpoint-in-Breast-Cancer-at-the-b-i-NRG1-i-b-b-i-Neuregulin-1-i-b-b-i-Heregulin-i-b-Gene",{"mag":351,"keywords":353,"openalex":354,"abstract":356,"title":358,"pm":360,"doi":362},{"VOID":352},"2109887104",{},{"VOID":355},"W2109887104",{"EN":357},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>Most studies of genomic rearrangements in common cancers have focused on regional gains and losses, but some rearrangements may break within specific genes. We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression. NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB\u002Fepidermal growth factor-receptor family, which includes ErbB2\u002FHER2. We have now screened for breaks at NRG1 in paraffin sections of breast tumors. Tissue microarrays were screened by fluorescence in situ hybridization, with hybridization probes proximal and distal to the expected breakpoints. This screen detects breaks but does not distinguish between translocation or deletion breakpoints. The screen was validated with array-comparative genomic hybridization on a custom 8p12 high-density genomic array to detect a lower copy number of the sequences that were lost distal to the breaks. We also precisely mapped the breaks in five tumors with different hybridization probes. Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers. In an unselected series of 213 cases with follow-up, breast cancers where the break was detected tended to be high-grade (65% grade III compared with 28% of negative cases). They were, like breast tumors in general, mainly ErbB2 low (11 of 13 were low) and estrogen receptor positive (11 of 13 positive).\u003C\u002Fjats:p>",{"EN":359},"A Recurrent Chromosome Breakpoint in Breast Cancer at the \u003Cb>\n                     \u003Ci>NRG1\u003C\u002Fi>\n                  \u003C\u002Fb>\u002F\u003Cb>\n                     \u003Ci>Neuregulin 1\u003C\u002Fi>\n                  \u003C\u002Fb>\u002F\u003Cb>\n                     \u003Ci>Heregulin\u003C\u002Fi>\n                  \u003C\u002Fb> Gene",{"VOID":361},"15466169",{"VOID":363},"10.1158\u002F0008-5472.can-04-1762","2024-12-10T22:53:54.092+00:00",[51],"https:\u002F\u002Faacrjournals.org\u002Fcancerres\u002Farticle\u002F64\u002F19\u002F6840\u002F511768\u002FA-Recurrent-Chromosome-Breakpoint-in-Breast-Cancer",[368,389,408,424,442,459,477,494,509,527,548,563,580,597,614,634],{"id":369,"sortIndex":137,"researcher":18,"roles":370,"affiliations":371,"properties":382},"3e3df05e-fdec-4c6f-a8d8-cee05c0bca7d",[],[372],{"id":373,"sortIndex":19,"affiliation":374,"properties":18},"109cbb38-3543-458f-8e2e-566763ee4834",{"id":375,"createTime":376,"updateTime":376,"relativeEntities":377,"slug":378,"properties":379,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"b151da57-6f26-4ce4-8066-1de94e4119da","2024-12-10T22:53:54.139+00:00",[],"1Cancer-Genomics-Program-Hutchison-MRC-Research-Centre-Departments-of-Pathology-and-Oncology-University-of-Cambridge-Cambridge-United-Kingdom-",{"title":380},{"EN":381},"1Cancer Genomics Program, Hutchison-MRC Research Centre, Departments of Pathology and Oncology, University of Cambridge, Cambridge, United Kingdom;",{"openalex":383,"orcid":385,"title":387},{"VOID":384},"A5087867534",{"VOID":386},"https:\u002F\u002Forcid.org\u002F0000-0003-2940-7392",{"EN":388},"Grace Callagy",{"id":390,"sortIndex":134,"researcher":18,"roles":391,"affiliations":392,"properties":403},"3c1932c7-0e6c-4df6-a0b3-36e89b89c3bc",[],[393],{"id":394,"sortIndex":19,"affiliation":395,"properties":18},"8513ecc4-2783-47b3-8b3f-9b95d5241b53",{"id":396,"createTime":397,"updateTime":397,"relativeEntities":398,"slug":399,"properties":400,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"22a72c04-f5ea-40e7-9e69-37b17d6a0705","2024-12-10T22:53:54.119+00:00",[],"2Molecular-Oncology-and-Medical-Oncology-Departments-Marseille-Cancer-Research-Institute-Institut-National-de-la-Sante-et-de-la-Recherche-Me-dicale-and-Institut-Paoli-Calmettes-Marseille-France-",{"title":401},{"EN":402},"2Molecular Oncology and Medical Oncology Departments, Marseille Cancer Research Institute, Institut National de la Santé et de la Recherche Médicale and Institut Paoli-Calmettes, Marseille, France;",{"openalex":404,"title":406},{"VOID":405},"A5053713474",{"EN":407},"José Adélaı̈de",{"id":409,"sortIndex":410,"researcher":18,"roles":411,"affiliations":412,"properties":419},"96f02d84-af18-44a4-a98d-68fa5cea5423",11,[],[413],{"id":414,"sortIndex":19,"affiliation":415,"properties":18},"697b5a2a-9875-4877-8ac5-8231f88a0d2c",{"id":396,"createTime":397,"updateTime":397,"relativeEntities":416,"slug":399,"properties":417,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":418},{"EN":402},{"openalex":420,"title":422},{"VOID":421},"A5088324209",{"EN":423},"Jocelyne Jacquemier",{"id":425,"sortIndex":426,"researcher":18,"roles":427,"affiliations":428,"properties":435},"b643af62-480e-4353-991b-e5908def4422",13,[],[429],{"id":430,"sortIndex":19,"affiliation":431,"properties":18},"9a8d88b7-f887-44cb-802d-f5a78a7700e7",{"id":396,"createTime":397,"updateTime":397,"relativeEntities":432,"slug":399,"properties":433,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":434},{"EN":402},{"openalex":436,"orcid":438,"title":440},{"VOID":437},"A5075116389",{"VOID":439},"https:\u002F\u002Forcid.org\u002F0000-0002-2344-1488",{"EN":441},"Max Chaffanet",{"id":443,"sortIndex":138,"researcher":18,"roles":444,"affiliations":445,"properties":452},"ddde9696-ab63-4637-80dd-9d260aea91e3",[],[446],{"id":447,"sortIndex":19,"affiliation":448,"properties":18},"79378cdc-1fb9-41e0-a739-a549c10b11ad",{"id":375,"createTime":376,"updateTime":376,"relativeEntities":449,"slug":378,"properties":450,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":451},{"EN":381},{"openalex":453,"orcid":455,"title":457},{"VOID":454},"A5029249080",{"VOID":456},"https:\u002F\u002Forcid.org\u002F0000-0002-5651-302X",{"EN":458},"Jessica C. 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Genomics 2000;66:15-25.",{"doi":688},"10.1006\u002Fgeno.2000.6178",{"id":18,"text":690,"url":18,"identifiers":691},"Chin SF, Daigo Y, Huang HE, et al A simple and reliable pretreatment protocol facilitates fluorescent in situ hybridisation on tissue microarrays of paraffin wax embedded tumor samples. Mol Pathol 2003;56:275-9.",{"doi":692},"10.1136\u002Fmp.56.5.275",{"id":18,"text":694,"url":18,"identifiers":695},"Isola J, DeVries S, Chu L, Ghazvini S, Waldman F Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples. Am J Pathol 1994;145:1301-8.",{},{"id":18,"text":697,"url":18,"identifiers":698},"Fiegler H, Carr P, Douglas EJ, et al DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 2003;36:361-74.",{"doi":699},"10.1002\u002Fgcc.10155",{"id":18,"text":701,"url":18,"identifiers":702},"Srinivasan R, Benton E, McCormick F, Thomas H, Gullick WJ Expression of the c-erbB-3\u002FHER-3 and c-erbB-4\u002FHER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Clin Cancer Res 1999;5:2877-83.",{},{"id":18,"text":704,"url":18,"identifiers":705},"Kononen J, Bubendorf L, Kallioniemi A, et al Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998;4:844-7.",{"doi":706},"10.1038\u002Fnm0798-844",{"id":18,"text":708,"url":18,"identifiers":709},"Raj EH, Skinner A, Mahji U, et al Neuregulin 1-alpha expression in locally advanced breast cancer. Breast 2001;10:41-5.",{"doi":710},"10.1054\u002Fbrst.2000.0182",{"id":18,"text":712,"url":18,"identifiers":713},"Liu X, Baker E, Eyre HJ, Sutherland GR, Zhou M Gamma-heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a chromosome translocation. Oncogene 1999;18:7110-4.",{"doi":714},"10.1038\u002Fsj.onc.1203136",{"id":18,"text":716,"url":18,"identifiers":717},"Wang XZ, Jolicoeur EM, Conte N, et al gamma-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL\u002FNRG1 genes in the MDA-MB-175 breast cancer cell line. Oncogene 1999;18:5718-21.",{"doi":718},"10.1038\u002Fsj.onc.1202950",{"id":18,"text":720,"url":18,"identifiers":721},"Schaefer G, Fitzpatrick VD, Sliwkowski MX Gamma-heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997;15:1385-94.",{"doi":722},"10.1038\u002Fsj.onc.1201317",{"id":18,"text":724,"url":18,"identifiers":725},"Falls DL Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003;284:14-30.",{"doi":726},"10.1016\u002FS0014-4827(02)00102-7",{"id":18,"text":728,"url":18,"identifiers":729},"Stern DF ErbBs in mammary development. Exp Cell Res 2003;284:89-98.",{"doi":730},"10.1016\u002FS0014-4827(02)00103-9",{"id":18,"text":732,"url":18,"identifiers":733},"Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 1988;54:105-15.",{"doi":734},"10.1016\u002F0092-8674(88)90184-5",{"id":18,"text":736,"url":18,"identifiers":737},"Bradbury JM, Arno J, Edwards PA Induction of epithelial abnormalities that resemble human breast lesions by the expression of the neu\u002FerbB-2 oncogene in reconstituted mouse mammary gland. Oncogene 1993;8:1551-8.",{},{"id":18,"text":739,"url":18,"identifiers":740},"Tognon C, Knezevich SR, Huntsman D, et al Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2002;2:367-76.",{"doi":741},"10.1016\u002FS1535-6108(02)00180-0",{"id":18,"text":743,"url":18,"identifiers":744},"Tonon G, Modi S, Wu L, et al t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 2003;33:208-13.",{"doi":745},"10.1038\u002Fng1083",{"id":18,"text":747,"url":18,"identifiers":748},"Look AT Oncogenic transcription factors in the human acute leukemias. Science (Wash DC) 1997;278:1059-64.",{"doi":749},"10.1126\u002Fscience.278.5340.1059",{"id":751,"createTime":752,"updateTime":752,"relativeEntities":753,"slug":754,"properties":755,"entityType":46,"verifyStatus":47,"verifyTime":752,"verifyNote":49,"syncStatus":17,"languages":769,"translateLanguages":18,"viewCount":19,"primaryUrl":770,"fullTextUrl":18,"authors":771,"publicationType":111,"publisherRelationship":898,"citationCount":914,"citationInfo":915,"publishDate":917,"publishYear":918,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":919,"isForceReanalyzing":344},"92706371-606f-4e7e-9de2-54d624254465","2024-12-10T22:53:51.756+00:00",[],"Epithelial-to-Mesenchymal-Transition-in-Human-Breast-Epithelial-Cells-Transformed-by-17%CE%B2-Estradiol",{"mag":756,"keywords":758,"openalex":759,"abstract":761,"title":763,"pm":765,"doi":767},{"VOID":757},"2133799748",{},{"VOID":760},"W2133799748",{"EN":762},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>The estrogen dependence of breast cancer has long been recognized; however, the role of 17β-estradiol (E2) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E2 treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF > bcMCF >>> trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E\u002FCD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor β1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation. 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Array comparative genomic hybridization analysis of genomic alterations in breast cancer subtypes. Cancer Res 2004; 64: 8541–9.",{"doi":1106},"10.1158\u002F0008-5472.CAN-04-1992",{"id":18,"text":1108,"url":18,"identifiers":1109},"Sheridan C, Kishimoto H, Fuchs RK, et al. CD44+\u002FCD24− breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 2006; 8: R59.",{"doi":1110},"10.1186\u002Fbcr1610",{"id":18,"text":1112,"url":18,"identifiers":1113},"Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: 2492–502.",{"doi":1114},"10.1001\u002Fjama.295.21.2492",{"id":18,"text":1116,"url":18,"identifiers":1117},"Soule HD, Maloney TM, Wolman SR, et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. 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However, there is limited understanding about MST2 control by key regulators of cell division and survival. Raf-1 binds and inhibits MST2 kinase, whereas dissociation from Raf-1 and binding to tumor suppressor protein RASSF1A activates MST2. Akt phosphorylates MST2 in response to mitogens, oncogenic Ras, or depletion of tumor suppressor phosphatase and tensin homologue deleted on chromosome 10. We identified T117 and T384 as Akt phosphorylation sites in MST2. Mutation of these sites inhibited MST2 binding to Raf-1 kinase but enhanced binding to tumor suppressor RASSF1A, accentuating downstream c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase signaling and promoting apoptosis. We determined that MST2 phosphorylation by Akt limits MST2 activity in two ways: first, by blocking its binding to RASSF1A and by promoting its association into the Raf-1 inhibitory complex, and second, by preventing homodimerization of MST2, which is needed for its activation. Dissociation of the Raf-1–MST2 complex promoted mitogenic signaling and coordinately licensed apoptotic risk. Using Ras effector domain mutants, we found that Akt is essential to prevent MST2 activation after mitogenic stimulation. Our findings elucidate how MST2 serves as a hub to integrate biological outputs of the Raf-1 and Akt pathways. Cancer Res; 70(3); 1195–203\u003C\u002Fjats:p>",{"EN":1134},"Proapoptotic Kinase MST2 Coordinates Signaling Crosstalk between RASSF1A, Raf-1, and Akt",{"VOID":1136},"20086174",{"VOID":1138},"10.1158\u002F0008-5472.can-09-3147",[51],"https:\u002F\u002Faacrjournals.org\u002Fcancerres\u002Farticle\u002F70\u002F3\u002F1195\u002F561055\u002FProapoptotic-Kinase-MST2-Coordinates-Signaling",[1142,1163,1178,1195,1212,1227],{"id":1143,"sortIndex":56,"researcher":18,"roles":1144,"affiliations":1145,"properties":1156},"ca50610f-ac23-4ddf-b5ff-669c4b742fb9",[],[1146],{"id":1147,"sortIndex":19,"affiliation":1148,"properties":18},"1a3e677c-741a-4be7-88d2-81d01a11ca0c",{"id":1149,"createTime":1150,"updateTime":1150,"relativeEntities":1151,"slug":1152,"properties":1153,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"d32a7861-2fbc-4338-8869-a442a2b1a565","2024-12-12T22:07:22.785+00:00",[],"Authors-Affiliations-1Proteomics-and-Signalling-Networks-Group-The-Beatson-Institute-for-Cancer-Research-2Integrative-and-Systems-Biology-Institute-for-Biomedical-and-Life-Sciences-University-of-Glasgow-Glasgow-United-Kingdom-and-3King-s-College-London-Randall-Division-of-Cell-and-Molecular-Biophysics-London-United-Kingdom",{"title":1154},{"EN":1155},"Authors' Affiliations: 1Proteomics and Signalling Networks Group, The Beatson Institute for Cancer Research; 2Integrative and Systems Biology, Institute for Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom and 3King's College London, Randall Division of Cell and Molecular Biophysics, London, United Kingdom",{"openalex":1157,"orcid":1159,"title":1161},{"VOID":1158},"A5062167352",{"VOID":1160},"https:\u002F\u002Forcid.org\u002F0000-0002-1313-6279",{"EN":1162},"Gregory 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Ng",{"id":1213,"sortIndex":135,"researcher":18,"roles":1214,"affiliations":1215,"properties":1222},"48cf68ff-6ceb-4955-abb7-2117ee0f0604",[],[1216],{"id":1217,"sortIndex":19,"affiliation":1218,"properties":18},"5f3dfb72-73fc-4465-abb2-98e9a9b63670",{"id":1149,"createTime":1150,"updateTime":1150,"relativeEntities":1219,"slug":1152,"properties":1220,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":1221},{"EN":1155},{"openalex":1223,"title":1225},{"VOID":1224},"A5017782298",{"EN":1226},"Christian Preisinger",{"id":1228,"sortIndex":97,"researcher":18,"roles":1229,"affiliations":1230,"properties":1237},"a2194b2b-c172-40c9-a04a-d3d242eb5e74",[],[1231],{"id":1232,"sortIndex":19,"affiliation":1233,"properties":18},"7ace675c-80fa-42ec-bb63-a646f9217783",{"id":1149,"createTime":1150,"updateTime":1150,"relativeEntities":1234,"slug":1152,"properties":1235,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":1236},{"EN":1155},{"openalex":1238,"orcid":1240,"title":1242},{"VOID":1239},"A5091893851",{"VOID":1241},"https:\u002F\u002Forcid.org\u002F0000-0002-2360-3141",{"EN":1243},"David Matallanas",{"url":18,"publisher":1245,"properties":1253},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":1246,"slug":10,"properties":1247,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":1250,"manageAffiliations":1251,"indexDatabases":1252,"url":18,"thumbnailPath":18,"statistic":18,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"eissn":1248,"title":1249},{"VOID":13},{"EN":15},[],[],[],{"volume":1254,"pages":1256,"issue":1258},{"VOID":1255},"70",{"VOID":1257},"1195-1203",{"VOID":1259},"3",106,{"total":1260,"publishYear":18,"statisticByYear":1262},{"2012":133,"2013":133,"2014":616,"2015":138,"2016":616,"2017":138,"2018":97,"2019":137,"2020":137,"2021":138,"2022":616,"2023":131,"2024":134},"2010-02-01",2010,[1266,1270,1274,1278,1282,1286,1290,1294,1298,1302,1306,1310,1314,1318,1322,1326,1330,1334,1338,1342,1346,1350,1354,1358,1362,1366,1370,1374,1378,1382,1386],{"id":18,"text":1267,"url":18,"identifiers":1268},"Taylor, 1996, Newly identified stress-responsive protein kinases, Krs-1 and Krs-2, Proc Natl Acad Sci U S A, 93, 10099, 10.1073\u002Fpnas.93.19.10099",{"doi":1269},"10.1073\u002Fpnas.93.19.10099",{"id":18,"text":1271,"url":18,"identifiers":1272},"Ura, 2001, MST1-JNK promotes apoptosis via caspase-dependent and independent pathways, Genes Cells, 6, 519, 10.1046\u002Fj.1365-2443.2001.00439.x",{"doi":1273},"10.1046\u002Fj.1365-2443.2001.00439.x",{"id":18,"text":1275,"url":18,"identifiers":1276},"Ura, 2007, Activation of the c-Jun N-terminal kinase pathway by MST1 is essential and sufficient for the induction of chromatin condensation during apoptosis, Mol Cell Biol, 27, 5514, 10.1128\u002FMCB.00199-07",{"doi":1277},"10.1128\u002FMCB.00199-07",{"id":18,"text":1279,"url":18,"identifiers":1280},"Ura, 2001, Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation, Proc Natl Acad Sci U S A, 98, 10148, 10.1073\u002Fpnas.181161698",{"doi":1281},"10.1073\u002Fpnas.181161698",{"id":18,"text":1283,"url":18,"identifiers":1284},"Lehtinen, 2006, A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span, Cell, 125, 987, 10.1016\u002Fj.cell.2006.03.046",{"doi":1285},"10.1016\u002Fj.cell.2006.03.046",{"id":18,"text":1287,"url":18,"identifiers":1288},"Matallanas, 2007, RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein, Mol Cell, 27, 962, 10.1016\u002Fj.molcel.2007.08.008",{"doi":1289},"10.1016\u002Fj.molcel.2007.08.008",{"id":18,"text":1291,"url":18,"identifiers":1292},"Baksh, 2005, The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death, Mol Cell, 18, 637, 10.1016\u002Fj.molcel.2005.05.010",{"doi":1293},"10.1016\u002Fj.molcel.2005.05.010",{"id":18,"text":1295,"url":18,"identifiers":1296},"Vos, 2006, The RASSF1A tumor suppressor activates Bax via MOAP-1, J Biol Chem, 281, 4557, 10.1074\u002Fjbc.M512128200",{"doi":1297},"10.1074\u002Fjbc.M512128200",{"id":18,"text":1299,"url":18,"identifiers":1300},"Agathanggelou, 2005, Role of the Ras-association domain family 1 tumor suppressor gene in human cancers, Cancer Res, 65, 3497, 10.1158\u002F0008-5472.CAN-04-4088",{"doi":1301},"10.1158\u002F0008-5472.CAN-04-4088",{"id":18,"text":1303,"url":18,"identifiers":1304},"Avruch, 2009, Rassf family of tumor suppressor polypeptides, J Biol Chem, 284, 11001, 10.1074\u002Fjbc.R800073200",{"doi":1305},"10.1074\u002Fjbc.R800073200",{"id":18,"text":1307,"url":18,"identifiers":1308},"Donninger, 2007, The RASSF1A tumor suppressor, J Cell Sci, 120, 3163, 10.1242\u002Fjcs.010389",{"doi":1309},"10.1242\u002Fjcs.010389",{"id":18,"text":1311,"url":18,"identifiers":1312},"O'Neill, 2004, Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1, Science, 306, 2267, 10.1126\u002Fscience.1103233",{"doi":1313},"10.1126\u002Fscience.1103233",{"id":18,"text":1315,"url":18,"identifiers":1316},"O'Neill, 2005, Taming the Hippo: Raf-1 controls apoptosis by suppressing MST2\u002FHippo, Cell Cycle, 4, 365, 10.4161\u002Fcc.4.3.1531",{"doi":1317},"10.4161\u002Fcc.4.3.1531",{"id":18,"text":1319,"url":18,"identifiers":1320},"O'Neill, 2004, Conferring specificity on the ubiquitous Raf\u002FMEK signalling pathway, Br J Cancer, 90, 283, 10.1038\u002Fsj.bjc.6601488",{"doi":1321},"10.1038\u002Fsj.bjc.6601488",{"id":18,"text":1323,"url":18,"identifiers":1324},"Jang, 2007, Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation, J Biol Chem, 282, 30836, 10.1074\u002Fjbc.M704542200",{"doi":1325},"10.1074\u002Fjbc.M704542200",{"id":18,"text":1327,"url":18,"identifiers":1328},"Franke, 2008, Intracellular signaling by Akt: bound to be specific, Sci Signal, 1, e29, 10.1126\u002Fscisignal.124pe29",{"doi":1329},"10.1126\u002Fscisignal.124pe29",{"id":18,"text":1331,"url":18,"identifiers":1332},"Ling, 2008, Biosignaling of mammalian Ste20-related kinases, Cell Signal, 20, 1237, 10.1016\u002Fj.cellsig.2007.12.019",{"doi":1333},"10.1016\u002Fj.cellsig.2007.12.019",{"id":18,"text":1335,"url":18,"identifiers":1336},"Basu, 2003, Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis, Mol Cell, 11, 11, 10.1016\u002FS1097-2765(02)00776-1",{"doi":1337},"10.1016\u002FS1097-2765(02)00776-1",{"id":18,"text":1339,"url":18,"identifiers":1340},"Carnero, 2008, The PTEN\u002FPI3K\u002FAKT signalling pathway in cancer, therapeutic implications, Curr Cancer Drug Targets, 8, 187, 10.2174\u002F156800908784293659",{"doi":1341},"10.2174\u002F156800908784293659",{"id":18,"text":1343,"url":18,"identifiers":1344},"Myers, 1998, The lipid phosphatase activity of PTEN is critical for its tumor supressor function, Proc Natl Acad Sci U S A, 95, 13513, 10.1073\u002Fpnas.95.23.13513",{"doi":1345},"10.1073\u002Fpnas.95.23.13513",{"id":18,"text":1347,"url":18,"identifiers":1348},"Ortiz-Vega, 2002, The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1, Oncogene, 21, 1381, 10.1038\u002Fsj.onc.1205192",{"doi":1349},"10.1038\u002Fsj.onc.1205192",{"id":18,"text":1351,"url":18,"identifiers":1352},"Peter, 2005, Multiphoton-FLIM quantification of the EGFP-mRFP1 FRET pair for localization of membrane receptor-kinase interactions, Biophys J, 88, 1224, 10.1529\u002Fbiophysj.104.050153",{"doi":1353},"10.1529\u002Fbiophysj.104.050153",{"id":18,"text":1355,"url":18,"identifiers":1356},"Joneson, 1996, Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS, Science, 271, 810, 10.1126\u002Fscience.271.5250.810",{"doi":1357},"10.1126\u002Fscience.271.5250.810",{"id":18,"text":1359,"url":18,"identifiers":1360},"Cantley, 1999, New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase\u002FAKT pathway, Proc Natl Acad Sci U S A, 96, 4240, 10.1073\u002Fpnas.96.8.4240",{"doi":1361},"10.1073\u002Fpnas.96.8.4240",{"id":18,"text":1363,"url":18,"identifiers":1364},"Garcia, 2009, Regulation of human myoblast differentiation by PEBP4, EMBO Rep, 10, 278, 10.1038\u002Fembor.2009.4",{"doi":1365},"10.1038\u002Fembor.2009.4",{"id":18,"text":1367,"url":18,"identifiers":1368},"Rommel, 1999, Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt, Science, 286, 1738, 10.1126\u002Fscience.286.5445.1738",{"doi":1369},"10.1126\u002Fscience.286.5445.1738",{"id":18,"text":1371,"url":18,"identifiers":1372},"Song, 2008, Differential cleavage of Mst1 by caspase-7\u002F-3 is responsible for TRAIL-induced activation of the MAPK superfamily, Cell Signal, 20, 892, 10.1016\u002Fj.cellsig.2008.01.001",{"doi":1373},"10.1016\u002Fj.cellsig.2008.01.001",{"id":18,"text":1375,"url":18,"identifiers":1376},"Graves, 1998, Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1, EMBO J, 17, 2224, 10.1093\u002Femboj\u002F17.8.2224",{"doi":1377},"10.1093\u002Femboj\u002F17.8.2224",{"id":18,"text":1379,"url":18,"identifiers":1380},"Watabe, 1999, Requirement of protein kinase (Krs\u002FMST) activation for MT-21-induced apoptosis, Oncogene, 18, 5211, 10.1038\u002Fsj.onc.1202901",{"doi":1381},"10.1038\u002Fsj.onc.1202901",{"id":18,"text":1383,"url":18,"identifiers":1384},"Wang, 2009, YAP, TAZ, Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease, Biochem Cell Biol, 87, 77, 10.1139\u002FO08-114",{"doi":1385},"10.1139\u002FO08-114",{"id":18,"text":1387,"url":18,"identifiers":1388},"Li, 2004, Transformation potential of Ras isoforms correlates with activation of phosphatidylinositol 3-kinase but not ERK, J Biol Chem, 279, 37398, 10.1074\u002Fjbc.M405730200",{"doi":1389},"10.1074\u002Fjbc.M405730200",{"id":1391,"createTime":1392,"updateTime":1392,"relativeEntities":1393,"slug":1394,"properties":1395,"entityType":46,"verifyStatus":47,"verifyTime":1409,"verifyNote":49,"syncStatus":17,"languages":1410,"translateLanguages":18,"viewCount":19,"primaryUrl":1411,"fullTextUrl":18,"authors":1412,"publicationType":111,"publisherRelationship":1609,"citationCount":1625,"citationInfo":1626,"publishDate":1630,"publishYear":1631,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":1632,"isForceReanalyzing":344},"5a7ca8b1-f7a5-4cb6-b708-23beb4bfa991","2024-12-12T22:06:01.646+00:00",[],"Role-of-the-Tumor-Suppressor-RASSF1A-in-Mst1-Mediated-Apoptosis",{"mag":1396,"keywords":1398,"openalex":1399,"abstract":1401,"title":1403,"pm":1405,"doi":1407},{"VOID":1397},"2103986437",{},{"VOID":1400},"W2103986437",{"EN":1402},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\u003Cjats:p>Mammalian sterile 20–like kinase 1 (Mst1) is activated by both caspase-mediated cleavage and phosphorylation in response to apoptotic stimuli, including Fas ligation. Here, we examined the possible role of the tumor suppressor RASSF1A in Mst1 activation and Mst1-mediated apoptosis induced by death receptor signaling. Immunoprecipitation and immunofluorescence analyses revealed that Mst1 was associated with RASSF1A in cultured mammalian cells, with both proteins colocalizing to microtubules throughout the cell cycle. Whereas purified recombinant RASSF1A inhibited the kinase activity of purified recombinant Mst1 in vitro, overexpression of RASSF1A increased the kinase activity of Mst1 in intact cells, suggesting that regulation of Mst1 by RASSF1A in vivo involves more than the simple association of the two proteins. Both the activation of Mst1 and the incidence of apoptosis induced by Fas ligation were markedly reduced in cells depleted of RASSF1A by RNA interference and were increased by restoration of RASSF1A expression in RASSF1A-deficient cells. Moreover, the stimulatory effect of RASSF1A overexpression on Fas-induced apoptosis was inhibited by depletion of Mst1. These findings indicate that RASSF1A facilitates Mst1 activation and thereby promotes apoptosis induced by death receptor signaling. (Cancer Res 2006; 66(5): 2562-9)\u003C\u002Fjats:p>",{"EN":1404},"Role of the Tumor Suppressor RASSF1A in Mst1-Mediated 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Target-specific gene silencing by siRNA plasmid DNA complexed with folate-modified poly(ethylenimine). J Control Release 2005; 104: 223–32.",{"doi":1773},"10.1016\u002Fj.jconrel.2005.02.006",{"id":18,"text":1775,"url":18,"identifiers":1776},"Taylor LK, Wang HC, Erikson RL. Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci U S A 1996; 93: 10099–104.",{"doi":1269},{"id":18,"text":1778,"url":18,"identifiers":1779},"O'Neill E, Rushworth L, Baccarini M, Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 2004; 306: 2267–70.",{"doi":1313},{"id":18,"text":1781,"url":18,"identifiers":1782},"Baksh S, Tommasi S, Fenton S, et al. The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death. 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Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. [Cancer Res 2008;68(11):4105–15]\u003C\u002Fjats:p>",{"EN":1799},"Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression",{"VOID":1801},"18519669",{"VOID":1803},"10.1158\u002F0008-5472.can-07-6814",[51],"https:\u002F\u002Faacrjournals.org\u002Fcancerres\u002Farticle\u002F68\u002F11\u002F4105\u002F540910\u002FRole-of-the-Polarity-Determinant-Crumbs-in",[1807,1826,1855,1870,1893,1908,1923,1938],{"id":1808,"sortIndex":134,"researcher":18,"roles":1809,"affiliations":1810,"properties":1821},"6542c736-f2d7-486c-891f-48fcdff763f0",[],[1811],{"id":1812,"sortIndex":19,"affiliation":1813,"properties":18},"a0bbe07a-9e81-4929-b1eb-77e4dc0b08b6",{"id":1814,"createTime":1815,"updateTime":1815,"relativeEntities":1816,"slug":1817,"properties":1818,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"7de3fcb6-c23f-46a8-b1e0-7ace04dd48fd","2024-12-20T21:33:12.813+00:00",[],"1Department-of-Molecular-Biology-and-Biochemistry-Center-for-Advanced-Biotechnology-and-Medicine-Rutgers-University-",{"title":1819},{"EN":1820},"1Department of Molecular Biology and Biochemistry, Center for Advanced Biotechnology and Medicine, Rutgers University;",{"openalex":1822,"title":1824},{"VOID":1823},"A5004028464",{"EN":1825},"Chandreyee Mukherjee",{"id":1827,"sortIndex":136,"researcher":18,"roles":1828,"affiliations":1829,"properties":1850},"654f0fc7-96ba-45f0-a900-c2bc2656c4d0",[],[1830,1840],{"id":1831,"sortIndex":97,"affiliation":1832,"properties":18},"eae15195-7a3c-482d-965f-7e5dbec2b158",{"id":1833,"createTime":1834,"updateTime":1834,"relativeEntities":1835,"slug":1836,"properties":1837,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"c6845d57-4c04-42fb-8ba4-532faa7aad12","2024-12-20T21:33:12.871+00:00",[],"3The-Cancer-Institute-of-New-Jersey-New-Brunswick-New-Jersey",{"title":1838},{"EN":1839},"3The Cancer Institute of New Jersey, New Brunswick, New Jersey",{"id":1841,"sortIndex":19,"affiliation":1842,"properties":18},"575fa58c-9247-47f8-8806-73133a82775a",{"id":1843,"createTime":1844,"updateTime":1844,"relativeEntities":1845,"slug":1846,"properties":1847,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"36757163-1c79-4f55-8ee7-d4c4c328005f","2024-12-20T21:33:12.831+00:00",[],"2Robert-Wood-Johnson-Medical-School-University-of-Medicine-and-Dentistry-of-New-Jersey-Piscataway-New-Jersey-and",{"title":1848},{"EN":1849},"2Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey and",{"openalex":1851,"title":1853},{"VOID":1852},"A5053535496",{"EN":1854},"Vassiliki Karantza‐Wadsworth",{"id":1856,"sortIndex":135,"researcher":18,"roles":1857,"affiliations":1858,"properties":1865},"695a6053-3feb-4181-91bc-36f0cac178e9",[],[1859],{"id":1860,"sortIndex":19,"affiliation":1861,"properties":18},"a7735add-db91-439e-acbc-38dad9bacfee",{"id":1814,"createTime":1815,"updateTime":1815,"relativeEntities":1862,"slug":1817,"properties":1863,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":1864},{"EN":1820},{"openalex":1866,"title":1868},{"VOID":1867},"A5006871346",{"EN":1869},"Deidre 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Karp",{"id":1939,"sortIndex":97,"researcher":18,"roles":1940,"affiliations":1941,"properties":1948},"fcecb870-cc8b-47f4-b885-5ffdf98b7ef0",[],[1942],{"id":1943,"sortIndex":19,"affiliation":1944,"properties":18},"31d1ad4d-f583-44f1-9c09-1489eeb53354",{"id":1814,"createTime":1815,"updateTime":1815,"relativeEntities":1945,"slug":1817,"properties":1946,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":1947},{"EN":1820},{"openalex":1949,"title":1951},{"VOID":1950},"A5109601740",{"EN":1952},"Ting Ting Tan",{"url":18,"publisher":1954,"properties":1962},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":1955,"slug":10,"properties":1956,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":1959,"manageAffiliations":1960,"indexDatabases":1961,"url":18,"thumbnailPath":18,"statistic":18,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"eissn":1957,"title":1958},{"VOID":13},{"EN":15},[],[],[],{"volume":1963,"pages":1965,"issue":1967},{"VOID":1964},"68",{"VOID":1966},"4105-4115",{"VOID":1968},"11",102,{"total":1969,"publishYear":18,"statisticByYear":1971},{"2012":137,"2013":131,"2014":137,"2015":137,"2016":137,"2017":131,"2018":131,"2019":136,"2020":97,"2021":131,"2022":135,"2023":137},"2008-06-01",2008,[1975,1979,1983,1987,1991,1995,1997,2001,2005,2009,2011,2015,2019,2023,2027,2031,2035,2039,2042,2046,2050,2054,2058,2062,2066,2070,2074,2078,2082,2086,2090,2094,2098,2102,2106,2110,2114,2118,2122,2126],{"id":18,"text":1976,"url":18,"identifiers":1977},"Degenhardt K, White E. A mouse model system to genetically dissect the molecular mechanisms regulating tumorigenesis. Clin Cancer Res 2006; 12: 5298–304.",{"doi":1978},"10.1158\u002F1078-0432.CCR-06-0439",{"id":18,"text":1980,"url":18,"identifiers":1981},"Tan TT, Degenhardt K, Nelson DA, et al. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 2005; 7: 227–38.",{"doi":1982},"10.1016\u002Fj.ccr.2005.02.008",{"id":18,"text":1984,"url":18,"identifiers":1985},"Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007; 21: 1621–35.",{"doi":1986},"10.1101\u002Fgad.1565707",{"id":18,"text":1988,"url":18,"identifiers":1989},"Degenhardt K, Chen G, Lindsten T, White E. BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer Cell 2002; 2: 193–203.",{"doi":1990},"10.1016\u002FS1535-6108(02)00126-5",{"id":18,"text":1992,"url":18,"identifiers":1993},"Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes Dev 2004; 18: 2095–107.",{"doi":1994},"10.1101\u002Fgad.1204904",{"id":18,"text":995,"url":18,"identifiers":1996},{"doi":997},{"id":18,"text":1998,"url":18,"identifiers":1999},"Zavadil J, Bottinger EP. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 2005; 24: 5764–74.",{"doi":2000},"10.1038\u002Fsj.onc.1208927",{"id":18,"text":2002,"url":18,"identifiers":2003},"Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005; 17: 548–58.",{"doi":2004},"10.1016\u002Fj.ceb.2005.08.001",{"id":18,"text":2006,"url":18,"identifiers":2007},"Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins\u002Foccludin by Snail. J Cell Sci 2003; 116: 1959–67.",{"doi":2008},"10.1242\u002Fjcs.00389",{"id":18,"text":1053,"url":18,"identifiers":2010},{"doi":1055},{"id":18,"text":2012,"url":18,"identifiers":2013},"Aigner K, Dampier B, Descovich L, et al. The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007; 26: 6979–88.",{"doi":2014},"10.1038\u002Fsj.onc.1210508",{"id":18,"text":2016,"url":18,"identifiers":2017},"Bilder D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev 2004; 18: 1909–25.",{"doi":2018},"10.1101\u002Fgad.1211604",{"id":18,"text":2020,"url":18,"identifiers":2021},"Lu H, Bilder D. Endocytic control of epithelial polarity and proliferation in Drosophila. Nat Cell Biol 2005; 7: 1232–9.",{"doi":2022},"10.1038\u002Fncb1324",{"id":18,"text":2024,"url":18,"identifiers":2025},"Margolis B, Borg JP. Apicobasal polarity complexes. J Cell Sci 2005; 118: 5157–9.",{"doi":2026},"10.1242\u002Fjcs.02597",{"id":18,"text":2028,"url":18,"identifiers":2029},"Fogg VC, Liu CJ, Margolis B. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J Cell Sci 2005; 118: 2859–69.",{"doi":2030},"10.1242\u002Fjcs.02412",{"id":18,"text":2032,"url":18,"identifiers":2033},"Perez D, White E. E1B 19K inhibits Fas-mediated apoptosis through FADD-dependent sequestration of FLICE. J Cell Biol 1998; 141: 1255–66.",{"doi":2034},"10.1083\u002Fjcb.141.5.1255",{"id":18,"text":2036,"url":18,"identifiers":2037},"Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 2003; 30: 256–68.",{"doi":2038},"10.1016\u002FS1046-2023(03)00032-X",{"id":18,"text":2040,"url":18,"identifiers":2041},"Albini A, Iwamoto Y, Kleinman HK, et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 1987; 47: 3239–45.",{},{"id":18,"text":2043,"url":18,"identifiers":2044},"Chang YH, Chao Y, Hsieh SL, Lin WW. Mechanism of LIGHT\u002Finterferon-γ-induced cell death in HT-29 cells. J Cell Biochem 2004; 93: 1188–202.",{"doi":2045},"10.1002\u002Fjcb.20282",{"id":18,"text":2047,"url":18,"identifiers":2048},"Klampfer L, Huang J, Swaby LA, Augenlicht L. Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem 2004; 279: 30358–68.",{"doi":2049},"10.1074\u002Fjbc.M401359200",{"id":18,"text":2051,"url":18,"identifiers":2052},"Kulaeva OI, Draghici S, Tang L, Kraniak JM, Land SJ, Tainsky MA. Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene 2003; 22: 4118–27.",{"doi":2053},"10.1038\u002Fsj.onc.1206594",{"id":18,"text":2055,"url":18,"identifiers":2056},"Nusinzon I, Horvath CM. Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1. Proc Natl Acad Sci U S A 2003; 100: 14742–7.",{"doi":2057},"10.1073\u002Fpnas.2433987100",{"id":18,"text":2059,"url":18,"identifiers":2060},"Sakamoto S, Potla R, Larner AC. Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes. J Biol Chem 2004; 279: 40362–7.",{"doi":2061},"10.1074\u002Fjbc.M406400200",{"id":18,"text":2063,"url":18,"identifiers":2064},"Simske JS, Koppen M, Sims P, Hodgkin J, Yonkof A, Hardin J. The cell junction protein VAB-9 regulates adhesion and epidermal morphology in C. elegans. Nat Cell Biol 2003; 5: 619–25.",{"doi":2065},"10.1038\u002Fncb1002",{"id":18,"text":2067,"url":18,"identifiers":2068},"Swisshelm K, Macek R, Kubbies M. Role of claudins in tumorigenesis. Adv Drug Deliv Rev 2005; 57: 919–28.",{"doi":2069},"10.1016\u002Fj.addr.2005.01.006",{"id":18,"text":2071,"url":18,"identifiers":2072},"Ladwein M, Pape UF, Schmidt DS, et al. The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7. Exp Cell Res 2005; 309: 345–57.",{"doi":2073},"10.1016\u002Fj.yexcr.2005.06.013",{"id":18,"text":2075,"url":18,"identifiers":2076},"Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004; 4: 118–32.",{"doi":2077},"10.1038\u002Fnrc1276",{"id":18,"text":2079,"url":18,"identifiers":2080},"Roh MH, Fan S, Liu CJ, Margolis B. The Crumbs3-PALS1 complex participates in the establishment of polarity in mammalian epithelial cells. J Cell Sci 2003; 116: 2895–906.",{"doi":2081},"10.1242\u002Fjcs.00500",{"id":18,"text":2083,"url":18,"identifiers":2084},"Klebes A, Knust E. A conserved motif in Crumbs is required for E-cadherin localisation and zonula adherens formation in Drosophila. Curr Biol 2000; 10: 76–85.",{"doi":2085},"10.1016\u002FS0960-9822(99)00277-8",{"id":18,"text":2087,"url":18,"identifiers":2088},"Lemmers C, Michel D, Lane-Guermonprez L, et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol Biol Cell 2004; 15: 1324–33.",{"doi":2089},"10.1091\u002Fmbc.e03-04-0235",{"id":18,"text":2091,"url":18,"identifiers":2092},"Hurd TW, Gao L, Roh MH, Macara IG, Margolis B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat Cell Biol 2003; 5: 137–42.",{"doi":2093},"10.1038\u002Fncb923",{"id":18,"text":2095,"url":18,"identifiers":2096},"Brabletz T, Jung A, Reu S, et al. Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A 2001; 98: 10356–61.",{"doi":2097},"10.1073\u002Fpnas.171610498",{"id":18,"text":2099,"url":18,"identifiers":2100},"Murtagh J, McArdle E, Gilligan E, Thornton L, Furlong F, Martin F. Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling. J Cell Biol 2004; 166: 133–43.",{"doi":2101},"10.1083\u002Fjcb.200403020",{"id":18,"text":2103,"url":18,"identifiers":2104},"Giebel B, Wodarz A. Tumor suppressors: control of signaling by endocytosis. Curr Biol 2006; 16: R91–2.",{"doi":2105},"10.1016\u002Fj.cub.2006.01.022",{"id":18,"text":2107,"url":18,"identifiers":2108},"Wodarz A, Hinz U, Engelbert M, Knust E. Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 1995; 82: 67–76.",{"doi":2109},"10.1016\u002F0092-8674(95)90053-5",{"id":18,"text":2111,"url":18,"identifiers":2112},"Yang M, Nelson D, Funakoshi Y, Padgett RW. Genome-wide microarray analysis of TGFβ signaling in the Drosophila brain. BMC Dev Biol 2004; 4: 14.",{"doi":2113},"10.1186\u002F1471-213X-4-14",{"id":18,"text":2115,"url":18,"identifiers":2116},"Liu H, Radisky DC, Wang F, Bissell MJ. Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells. J Cell Biol 2004; 164: 603–12.",{"doi":2117},"10.1083\u002Fjcb.200306090",{"id":18,"text":2119,"url":18,"identifiers":2120},"Guo W, Pylayeva Y, Pepe A, et al. β4 Integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 2006; 126: 489–502.",{"doi":2121},"10.1016\u002Fj.cell.2006.05.047",{"id":18,"text":2123,"url":18,"identifiers":2124},"Aranda V, Haire T, Nolan ME, et al. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 2006; 8: 1235–45.",{"doi":2125},"10.1038\u002Fncb1485",{"id":18,"text":2127,"url":18,"identifiers":2128},"Martin TA, Jiang WG. Tight junctions and their role in cancer metastasis. Histol Histopathol 2001; 16: 1183–95.",{},{"id":2130,"createTime":2131,"updateTime":2131,"relativeEntities":2132,"slug":2133,"properties":2134,"entityType":46,"verifyStatus":47,"verifyTime":2131,"verifyNote":49,"syncStatus":17,"languages":2150,"translateLanguages":18,"viewCount":19,"primaryUrl":2151,"fullTextUrl":18,"authors":2152,"publicationType":111,"publisherRelationship":2651,"citationCount":2667,"citationInfo":2668,"publishDate":2674,"publishYear":2675,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":2676,"isForceReanalyzing":344},"547e82cf-845d-4181-bc05-2b7cfbd12ffb","2025-01-04T20:32:17.044+00:00",[],"Phase-I-Trial-of-Recombinant-Modified-Vaccinia-Ankara-Encoding-Epstein-Barr-Viral-Tumor-Antigens-in-Nasopharyngeal-Carcinoma-Patients",{"mag":2135,"keywords":2137,"pmc":2138,"openalex":2140,"abstract":2142,"title":2144,"pm":2146,"doi":2148},{"VOID":2136},"2110002578",{},{"VOID":2139},"6485495",{"VOID":2141},"W2110002578",{"EN":2143},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>Epstein–Barr virus (EBV) is associated with several malignancies including nasopharyngeal carcinoma, a high incidence tumor in Chinese populations, in which tumor cells express the two EBV antigens EB nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2). Here, we report the phase I trial of a recombinant vaccinia virus, MVA-EL, which encodes an EBNA1\u002FLMP2 fusion protein designed to boost T-cell immunity to these antigens. The vaccine was delivered to Hong Kong patients with nasopharyngeal carcinoma to determine a safe and immunogenic dose. The patients, all in remission more than 12 weeks after primary therapy, received three intradermal MVA-EL vaccinations at three weekly intervals, using five escalating dose levels between 5 × 107 and 5 × 108 plaque-forming unit (pfu). Blood samples were taken during prescreening, immediately before vaccination, one week afterward and at intervals up to one year later. Immunogenicity was tested by IFN-γ ELIspot assays using complete EBNA1 and LMP2 15-mer peptide mixes and known epitope peptides relevant to patient MHC type. Eighteen patients were treated, three per dose level one to four and six at the highest dose, without dose-limiting toxicity. T-cell responses to one or both vaccine antigens were increased in 15 of 18 patients and, in many cases, were mapped to known CD4 and CD8 epitopes in EBNA1 and\u002For LMP2. The range of these responses suggested a direct relationship with vaccine dose, with all six patients at the highest dose level giving strong EBNA1\u002FLMP2 responses. We concluded that MVA-EL is both safe and immunogenic, allowing the highest dose to be forwarded to phase II studies examining clinical benefit. 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2Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham; 3Health Protection Agency, West Midlands Public Health Laboratory, Heart of England Foundation Trust, Birmingham; 4Section of Virology, Imperial College, London; and 5Cancer Research UK Drug Development Office, London, United Kingdom",{"id":2188,"sortIndex":56,"affiliation":2189,"properties":18},"5a3bf0be-d101-4005-a9eb-631551774406",{"id":2190,"createTime":2191,"updateTime":2191,"relativeEntities":2192,"slug":2193,"properties":2194,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"a60a8568-3e0b-4d02-a826-a048b351e339","2025-01-04T20:32:17.082+00:00",[],"Cancer-Research-UK-Drug-Development-Office-London-United-Kingdom",{"title":2195},{"EN":2196},"Cancer Research UK Drug Development Office, London, United Kingdom",{"openalex":2198,"orcid":2200,"title":2202},{"VOID":2199},"A5077991681",{"VOID":2201},"https:\u002F\u002Forcid.org\u002F0009-0004-4417-7809",{"EN":2203},"Hui Jia",{"id":2205,"sortIndex":616,"researcher":18,"roles":2206,"affiliations":2207,"properties":2232},"b8018273-b1a5-4bb9-83ff-eeab9c55be7d",[],[2208,2214,2220,2226],{"id":2209,"sortIndex":19,"affiliation":2210,"properties":18},"0040840d-f6d8-4512-8c48-87dd4d8478e2",{"id":2180,"createTime":2181,"updateTime":2181,"relativeEntities":2211,"slug":2183,"properties":2212,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2213},{"EN":2186},{"id":2215,"sortIndex":135,"affiliation":2216,"properties":18},"de888c5b-adbf-4c1c-901a-58e47628d30f",{"id":2160,"createTime":2161,"updateTime":2161,"relativeEntities":2217,"slug":2163,"properties":2218,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2219},{"EN":2166},{"id":2221,"sortIndex":56,"affiliation":2222,"properties":18},"8ba569b8-e16d-48b8-94ee-03ca81405ab8",{"id":2190,"createTime":2191,"updateTime":2191,"relativeEntities":2223,"slug":2193,"properties":2224,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2225},{"EN":2196},{"id":2227,"sortIndex":97,"affiliation":2228,"properties":18},"e3e882b8-38c4-47b0-9d56-1a6cd61b276e",{"id":2170,"createTime":2171,"updateTime":2171,"relativeEntities":2229,"slug":2173,"properties":2230,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2231},{"EN":2176},{"openalex":2233,"orcid":2235,"title":2237},{"VOID":2234},"A5023057149",{"VOID":2236},"https:\u002F\u002Forcid.org\u002F0000-0001-8031-1738",{"EN":2238},"Deborah Stocken",{"id":2240,"sortIndex":19,"researcher":18,"roles":2241,"affiliations":2242,"properties":2267},"5c78f973-fcd9-4410-8fdb-4baeab14fb02",[],[2243,2249,2255,2261],{"id":2244,"sortIndex":135,"affiliation":2245,"properties":18},"e02aeecd-65cd-4f44-a066-a20fba4a9617",{"id":2160,"createTime":2161,"updateTime":2161,"relativeEntities":2246,"slug":2163,"properties":2247,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2248},{"EN":2166},{"id":2250,"sortIndex":56,"affiliation":2251,"properties":18},"ad26be0d-9009-4dd7-b3c1-77963f8dd091",{"id":2190,"createTime":2191,"updateTime":2191,"relativeEntities":2252,"slug":2193,"properties":2253,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2254},{"EN":2196},{"id":2256,"sortIndex":19,"affiliation":2257,"properties":18},"c6d9211e-0612-4d5f-b0aa-57b8d1dc5ac1",{"id":2180,"createTime":2181,"updateTime":2181,"relativeEntities":2258,"slug":2183,"properties":2259,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2260},{"EN":2186},{"id":2262,"sortIndex":97,"affiliation":2263,"properties":18},"06b0d56c-44d2-41f3-807d-3ffd249d988f",{"id":2170,"createTime":2171,"updateTime":2171,"relativeEntities":2264,"slug":2173,"properties":2265,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2266},{"EN":2176},{"openalex":2268,"orcid":2270,"title":2272},{"VOID":2269},"A5033886818",{"VOID":2271},"https:\u002F\u002Forcid.org\u002F0000-0002-8134-7019",{"EN":2273},"Edwin P. 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efficient presentation of Epstein–Barr virus cytotoxic T-cell epitopes by NPC cells, Cancer Res, 58, 310",{},{"id":18,"text":2803,"url":18,"identifiers":2804},"Yao, 2000, Heterogeneity of HLA and EBER expression in Epstein–Barr virus-associated nasopharyngeal carcinoma, Int J Cancer, 88, 949, 10.1002\u002F1097-0215(20001215)88:6\u003C949::AID-IJC18>3.0.CO;2-6",{"doi":2805},"10.1002\u002F1097-0215(20001215)88:6\u003C949::AID-IJC18>3.0.CO;2-6",{"id":18,"text":2807,"url":18,"identifiers":2808},"Li, 2007, Functional inactivation of EBV-specific T-lymphocytes in nasopharyngeal carcinoma: implications for tumor immunotherapy, PLoS ONE, 2, e1122, 10.1371\u002Fjournal.pone.0001122",{"doi":2809},"10.1371\u002Fjournal.pone.0001122",{"id":18,"text":2811,"url":18,"identifiers":2812},"Harrop, 2006, Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I\u002FII trial, Clin Cancer Res, 12, 3416, 10.1158\u002F1078-0432.CCR-05-2732",{"doi":2813},"10.1158\u002F1078-0432.CCR-05-2732",{"id":18,"text":2815,"url":18,"identifiers":2816},"Bejon, 2006, Safety profile of the viral vectors of attenuated fowlpox strain FP9 and modified vaccinia virus Ankara recombinant for either of 2 preerythrocytic malaria antigens, ME-TRAP or the circumsporozoite protein, in children and adults in Kenya, Clin Infect Dis, 42, 1102, 10.1086\u002F501459",{"doi":2817},"10.1086\u002F501459",{"id":18,"text":2819,"url":18,"identifiers":2820},"Dunachie, 2006, A DNA prime-modified vaccinia virus ankara boost vaccine encoding thrombospondin-related adhesion protein but not circumsporozoite protein partially protects healthy malaria-naive adults against Plasmodium falciparum sporozoite challenge, Infect Immun, 74, 5933, 10.1128\u002FIAI.00590-06",{"doi":2821},"10.1128\u002FIAI.00590-06",{"id":18,"text":2823,"url":18,"identifiers":2824},"Harrop, 2008, Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses, Cancer Immunol Immunother, 57, 977, 10.1007\u002Fs00262-007-0428-7",{"doi":2825},"10.1007\u002Fs00262-007-0428-7",{"id":18,"text":2827,"url":18,"identifiers":2828},"Ramlau, 2008, A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III\u002FIV non–small cell lung cancer, J Thorac Oncol, 3, 735, 10.1097\u002FJTO.0b013e31817c6b4f",{"doi":2829},"10.1097\u002FJTO.0b013e31817c6b4f",{"id":18,"text":2831,"url":18,"identifiers":2832},"McShane, 2004, Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans, Nat Med, 10, 1240, 10.1038\u002Fnm1128",{"doi":2833},"10.1038\u002Fnm1128",{"id":18,"text":2835,"url":18,"identifiers":2836},"McConkey, 2003, Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans, Nat Med, 9, 729, 10.1038\u002Fnm881",{"doi":2837},"10.1038\u002Fnm881",{"id":18,"text":2839,"url":18,"identifiers":2840},"Bollard, 2004, Cytotoxic T lymphocyte therapy for Epstein–Barr virus+ Hodgkin's disease, J Exp Med, 200, 1623, 10.1084\u002Fjem.20040890",{"doi":2841},"10.1084\u002Fjem.20040890",{"id":18,"text":2843,"url":18,"identifiers":2844},"Fox, 2010, A novel latent membrane 2 transcript expressed in Epstein–Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy, Blood, 116, 3695, 10.1182\u002Fblood-2010-06-292268",{"doi":2845},"10.1182\u002Fblood-2010-06-292268",{"id":18,"text":2847,"url":18,"identifiers":2848},"Lau, 2007, Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients, Br J Cancer, 96, 617, 10.1038\u002Fsj.bjc.6603580",{"doi":2849},"10.1038\u002Fsj.bjc.6603580",{"id":2851,"createTime":2852,"updateTime":2852,"relativeEntities":2853,"slug":2854,"properties":2855,"entityType":46,"verifyStatus":47,"verifyTime":2869,"verifyNote":49,"syncStatus":17,"languages":2870,"translateLanguages":18,"viewCount":19,"primaryUrl":2871,"fullTextUrl":18,"authors":2872,"publicationType":111,"publisherRelationship":2963,"citationCount":2978,"citationInfo":2979,"publishDate":2981,"publishYear":671,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":2982,"isForceReanalyzing":344},"4b90100d-3ff1-4927-a52e-e5363f594862","2024-12-05T20:23:15.596+00:00",[],"Promotion-of-Microsatellite-Instability-by-Hepatitis-C-Virus-Core-Protein-in-Human-Non-neoplastic-Hepatocyte-Cells",{"mag":2856,"keywords":2858,"openalex":2859,"abstract":2861,"title":2863,"pm":2865,"doi":2867},{"VOID":2857},"2162537660",{},{"VOID":2860},"W2162537660",{"EN":2862},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA)17 dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to non-neoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.\u003C\u002Fjats:p>",{"EN":2864},"Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells",{"VOID":2866},"14973066",{"VOID":2868},"10.1158\u002F0008-5472.can-03-2992","2024-12-05T20:23:15.595+00:00",[51],"https:\u002F\u002Faacrjournals.org\u002Fcancerres\u002Farticle\u002F64\u002F4\u002F1307\u002F512246\u002FPromotion-of-Microsatellite-Instability-by",[2873,2895,2912,2929,2946],{"id":2874,"sortIndex":97,"researcher":18,"roles":2875,"affiliations":2876,"properties":2888},"a392f1de-f317-4fcc-a871-330d2b56bf86",[],[2877],{"id":2878,"sortIndex":19,"affiliation":2879,"properties":18},"da1f72e4-dacd-460c-a2b4-534f18921f4d",{"id":2880,"createTime":2881,"updateTime":2882,"relativeEntities":2883,"slug":2884,"properties":2885,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"adcdf54d-bfd5-441a-9ccf-bbcff3aa4733","2024-01-29T08:38:48.085+00:00","2024-12-05T20:23:15.628+00:00",[],"Department-of-Molecular-Biology-Okayama-University-Graduate-School-of-Medicine-and-Dentistry-Okayama-Japan",{"title":2886},{"VI":2887},"Department of Molecular Biology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan",{"openalex":2889,"orcid":2891,"title":2893},{"VOID":2890},"A5039236463",{"VOID":2892},"https:\u002F\u002Forcid.org\u002F0000-0002-2353-3024",{"EN":2894},"Hiromichi Dansako",{"id":2896,"sortIndex":134,"researcher":18,"roles":2897,"affiliations":2898,"properties":2905},"5ae98422-517e-4e7f-ae1c-b36c06b430e9",[],[2899],{"id":2900,"sortIndex":19,"affiliation":2901,"properties":18},"0b82f1eb-2579-4299-b117-cc8fb2a96cca",{"id":2880,"createTime":2881,"updateTime":2882,"relativeEntities":2902,"slug":2884,"properties":2903,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2904},{"VI":2887},{"openalex":2906,"orcid":2908,"title":2910},{"VOID":2907},"A5101678773",{"VOID":2909},"https:\u002F\u002Forcid.org\u002F0000-0003-3630-7517",{"EN":2911},"Nobuyuki Kato",{"id":2913,"sortIndex":19,"researcher":18,"roles":2914,"affiliations":2915,"properties":2922},"459c2620-a617-474f-8bfd-648be649db13",[],[2916],{"id":2917,"sortIndex":19,"affiliation":2918,"properties":18},"552d6f72-9409-4010-b8c8-06669d7c7a71",{"id":2880,"createTime":2881,"updateTime":2882,"relativeEntities":2919,"slug":2884,"properties":2920,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2921},{"VI":2887},{"openalex":2923,"orcid":2925,"title":2927},{"VOID":2924},"A5069193172",{"VOID":2926},"https:\u002F\u002Forcid.org\u002F0000-0003-0663-0102",{"EN":2928},"Atsushi Naganuma",{"id":2930,"sortIndex":56,"researcher":18,"roles":2931,"affiliations":2932,"properties":2939},"b2a058b6-3d20-444f-a157-e97feba60eb8",[],[2933],{"id":2934,"sortIndex":19,"affiliation":2935,"properties":18},"02428324-e9f8-4738-9064-378518361e9b",{"id":2880,"createTime":2881,"updateTime":2882,"relativeEntities":2936,"slug":2884,"properties":2937,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2938},{"VI":2887},{"openalex":2940,"orcid":2942,"title":2944},{"VOID":2941},"A5103191617",{"VOID":2943},"https:\u002F\u002Forcid.org\u002F0000-0002-1284-0520",{"EN":2945},"Takashi Nakamura",{"id":2947,"sortIndex":135,"researcher":18,"roles":2948,"affiliations":2949,"properties":2956},"8adc6cbc-6077-4680-80c7-38feaf7b932c",[],[2950],{"id":2951,"sortIndex":19,"affiliation":2952,"properties":18},"dcbb0f6e-1012-48e7-a70c-1af3c8f31e07",{"id":2880,"createTime":2881,"updateTime":2882,"relativeEntities":2953,"slug":2884,"properties":2954,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":2955},{"VI":2887},{"openalex":2957,"orcid":2959,"title":2961},{"VOID":2958},"A5079858903",{"VOID":2960},"https:\u002F\u002Forcid.org\u002F0000-0002-3310-6632",{"EN":2962},"Akito Nozaki",{"url":18,"publisher":2964,"properties":2972},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":2965,"slug":10,"properties":2966,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":2969,"manageAffiliations":2970,"indexDatabases":2971,"url":18,"thumbnailPath":18,"statistic":18,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"eissn":2967,"title":2968},{"VOID":13},{"EN":15},[],[],[],{"volume":2973,"pages":2974,"issue":2976},{"VOID":662},{"VOID":2975},"1307-1314",{"VOID":2977},"4",29,{"total":2978,"publishYear":18,"statisticByYear":2980},{"2012":97,"2013":56,"2014":97,"2015":97,"2017":97,"2018":97,"2019":97,"2023":97,"2024":97},"2004-02-15",[2983,2987,2991,2995,2999,3003,3007,3011,3015,3019,3023,3027,3031,3034,3038,3042,3046,3050,3054,3058,3062,3066,3070,3074,3078,3082,3086,3090,3094,3098,3102,3106,3110,3113,3117,3121,3125,3129,3133,3137,3141,3144,3148,3152,3156,3160,3164,3168,3172,3176,3180,3183,3187],{"id":18,"text":2984,"url":18,"identifiers":2985},"Choo 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Immunol., 42: 875-877,  1998.",{"doi":3116},"10.1111\u002Fj.1348-0421.1998.tb02364.x",{"id":18,"text":3118,"url":18,"identifiers":3119},"Umar A., Boyer J. C., Thomas D. C., Nguyen D. C., Risinger J. I., Boyd J., Ionov Y., Perucho M., Kunkel T. A. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J. Biol. Chem., 269: 14367-14370,  1994.",{"doi":3120},"10.1016\u002FS0021-9258(17)36630-9",{"id":18,"text":3122,"url":18,"identifiers":3123},"Kahn S. M., Klein M. G., Jiang W., Xing W. Q., Xu D. B., Perucho M., Weinstein I. B. Design of a selectable reporter for the detection of mutations in mammalian simple repeat sequences. Carcinogenesis (Lond.), 16: 1223-1238,  1995.",{"doi":3124},"10.1093\u002Fcarcin\u002F16.5.1223",{"id":18,"text":3126,"url":18,"identifiers":3127},"Hanford M. G., Rushton B. C., Gowen L. C., Farber R. A. Microsatellite mutation rates in cancer cell lines deficient or proficient in mismatch repair. Oncogene, 16: 2389-2393,  1998.",{"doi":3128},"10.1038\u002Fsj.onc.1201751",{"id":18,"text":3130,"url":18,"identifiers":3131},"Diem C., Runger T. M. A novel plasmid shuttle vector for the detection and analysis of microsatellite instability in cell lines. Mutat. Res., 407: 117-124,  1998.",{"doi":3132},"10.1016\u002FS0921-8777(97)00068-2",{"id":18,"text":3134,"url":18,"identifiers":3135},"Zienolddiny S., Svendsrud D. H., Ryberg D., Mikalsen A. B., Haugen A. Nickel(II) induces microsatellite mutations in human lung cancer cell lines. Mutat. Res., 452: 91-100,  2000.",{"doi":3136},"10.1016\u002FS0027-5107(00)00060-9",{"id":18,"text":3138,"url":18,"identifiers":3139},"Oki E., Oda S., Maehara Y., Sugimachi K. Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair. Oncogene, 18: 2143-2147,  1999.",{"doi":3140},"10.1038\u002Fsj.onc.1202583",{"id":18,"text":3142,"url":18,"identifiers":3143},"Hoang J. 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A., Egeland D. B., Royals B. A., Claycomb W. C. The MRE11-NBS1-RAD50 pathway is perturbed in SV40 large T antigen-immortalized AT-1, AT-2 and HL-1 cardiomyocytes. Nucl. Acids Res., 28: 2882-2892,  2000.",{"doi":3159},"10.1093\u002Fnar\u002F28.15.2882",{"id":18,"text":3161,"url":18,"identifiers":3162},"Kobayashi N., Fujiwara T., Westerman K. A., Inoue Y., Sakaguchi M., Noguchi H., Miyazaki M., Cai J., Tanaka N., Fox I. J., Leboulch P. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science (Wash. DC), 287: 1258-1262,  2000.",{"doi":3163},"10.1126\u002Fscience.287.5456.1258",{"id":18,"text":3165,"url":18,"identifiers":3166},"Chander N., Billig B., McMaster J., Novak J. Inactivation of p53 gene in human and murine osteosarcoma cells. Br. J. Cancer, 65: 208-214,  1992.",{"doi":3167},"10.1038\u002Fbjc.1992.43",{"id":18,"text":3169,"url":18,"identifiers":3170},"Lohmann V., Korner F., Koch J., Herian U., Theilmann L., Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science (Wash. DC), 285: 110-113,  1999.",{"doi":3171},"10.1126\u002Fscience.285.5424.110",{"id":18,"text":3173,"url":18,"identifiers":3174},"Ikeda M., Yi M., Li K., Lemon S. Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells. J. Virol., 76: 2997-3006,  2002.",{"doi":3175},"10.1128\u002FJVI.76.6.2997-3006.2002",{"id":18,"text":3177,"url":18,"identifiers":3178},"Kato N., Sugiyama K., Namba K., Dansako H., Nakamura T., Takami M., Naka K., Nozaki A., Shimotohno K. Establishment of a hepatitis C virus subgenomic replicon derived from human hepatocytes infected in vitro. Biochem. Biophys. Res. Commun., 306: 756-766,  2003.",{"doi":3179},"10.1016\u002FS0006-291X(03)01047-7",{"id":18,"text":3181,"url":18,"identifiers":3182},"Zein N. N., Poterucha J. J., Gross J. B., Jr., Wiesner R. H., Therneau T. M., Gossard A. A., Wendt N. K., Mitchell P. S., Germer J. J., Persing D. H. Increased risk of hepatocellular carcinoma in patients infected with hepatitis C genotype 1b. Am. J. Gastroenterol., 91: 2560-2562,  1996.",{},{"id":18,"text":3184,"url":18,"identifiers":3185},"Silini E., Bottelli R., Asti M., Bruno S., Candusso M. E., Brambilla S., Bono F., Iamoni G., Tinelli C., Mondelli M. U., Ideo G. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a case-control study. Gastroenterology, 111: 199-205,  1996.",{"doi":3186},"10.1053\u002Fgast.1996.v111.pm8698200",{"id":18,"text":3188,"url":18,"identifiers":3189},"Reid A. E., Koziel M. J., Aiza I., Jeffers L., Reddy R., Schiff E., Lau J. Y., Dienstag J. L., Liang T. J. Hepatitis C virus genotypes and viremia and hepatocellular carcinoma in the United States. Am. J. Gastroenterol., 94: 1619-1626,  1999.",{"doi":3190},"10.1111\u002Fj.1572-0241.1999.01153.x",{"id":3192,"createTime":3193,"updateTime":3193,"relativeEntities":3194,"slug":3195,"properties":3196,"entityType":46,"verifyStatus":47,"verifyTime":3210,"verifyNote":49,"syncStatus":17,"languages":3211,"translateLanguages":18,"viewCount":19,"primaryUrl":3212,"fullTextUrl":18,"authors":3213,"publicationType":111,"publisherRelationship":3345,"citationCount":3361,"citationInfo":3362,"publishDate":3364,"publishYear":3365,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":3366,"isForceReanalyzing":344},"a834a49e-d02f-4625-9c5f-c60de4123004","2024-12-13T17:47:52.067+00:00",[],"RASSF1A-Directly-Antagonizes-RhoA-Activity-through-the-Assembly-of-a-Smurf1-Mediated-Destruction-Complex-to-Suppress-Tumorigenesis",{"mag":3197,"keywords":3199,"openalex":3200,"abstract":3202,"title":3204,"pm":3206,"doi":3208},{"VOID":3198},"2303102647",{},{"VOID":3201},"W2303102647",{"EN":3203},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>RASSF1A is a tumor suppressor implicated in many tumorigenic processes; however, the basis for its tumor suppressor functions are not fully understood. Here we show that RASSF1A is a novel antagonist of protumorigenic RhoA activity. Direct interaction between the C-terminal amino acids (256–277) of RASSF1A and active GTP-RhoA was critical for this antagonism. In addition, interaction between the N-terminal amino acids (69-82) of RASSF1A and the ubiquitin E3 ligase Smad ubiquitination regulatory factor 1 (Smurf1) disrupted GTPase activity by facilitating Smurf1-mediated ubiquitination of GTP-RhoA. We noted that the RhoA-binding domain of RASSF1A displayed high sequence homology with Rho-binding motifs in other RhoA effectors, such as Rhotekin. As predicted on this basis, RASSF1A competed with Rhotekin to bind RhoA and to block its activation. RASSF1A mutants unable to bind RhoA or Smurf1 failed to suppress RhoA-induced tumor cell proliferation, drug resistance, epithelial–mesenchymal transition, migration, invasion, and metastasis. Clinically, expression levels of RASSF1A and RhoA were inversely correlated in many types of primary and metastatic tumors and tumor cell lines. Collectively, our findings showed how RASSF1A may suppress tumorigenesis by intrinsically inhibiting the tumor-promoting activity of RhoA, thereby illuminating the potential mechanistic consequences of RASSF1A inactivation in many cancers. Cancer Res; 76(7); 1847–59. ©2016 AACR.\u003C\u002Fjats:p>",{"EN":3205},"RASSF1A Directly Antagonizes RhoA Activity through the Assembly of a Smurf1-Mediated Destruction Complex to Suppress 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cancers and malignant phenotype suppression, J Natl Cancer Inst, 93, 691, 10.1093\u002Fjnci\u002F93.9.691",{"doi":1718},{"id":18,"text":3387,"url":18,"identifiers":3388},"Byun, 2001, Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma, Cancer Res, 61, 7034",{},{"id":18,"text":3390,"url":18,"identifiers":3391},"Praskova, 2004, Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras, Biochem J, 381, 453, 10.1042\u002FBJ20040025",{"doi":1702},{"id":18,"text":3393,"url":18,"identifiers":3394},"Baksh, 2005, The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to bax conformational change and cell death, Mol Cell, 18, 637, 10.1016\u002Fj.molcel.2005.05.010",{"doi":1293},{"id":18,"text":1295,"url":18,"identifiers":3396},{"doi":1297},{"id":18,"text":3398,"url":18,"identifiers":3399},"Shivakumar, 2002, The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation, Mol Cell Biol, 22, 4309, 10.1128\u002FMCB.22.12.4309-4318.2002",{"doi":1738},{"id":18,"text":3401,"url":18,"identifiers":3402},"Song, 2008, The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex, EMBO J, 27, 1863, 10.1038\u002Femboj.2008.115",{"doi":3403},"10.1038\u002Femboj.2008.115",{"id":18,"text":3405,"url":18,"identifiers":3406},"Song, 2004, The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex, Nat Cell Biol, 6, 129, 10.1038\u002Fncb1091",{"doi":1746},{"id":18,"text":3408,"url":18,"identifiers":3409},"Liu, 2003, Control of microtubule stability by the RASSF1A tumor suppressor, Oncogene, 22, 8125, 10.1038\u002Fsj.onc.1206984",{"doi":3410},"10.1038\u002Fsj.onc.1206984",{"id":18,"text":3412,"url":18,"identifiers":3413},"Vos, 2004, A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability, Cancer Res, 64, 4244, 10.1158\u002F0008-5472.CAN-04-0339",{"doi":1758},{"id":18,"text":3415,"url":18,"identifiers":3416},"El-Kalla, 2010, Functional importance of RASSF1A microtubule localization and polymorphisms, Oncogene, 29, 5729, 10.1038\u002Fonc.2010.316",{"doi":3417},"10.1038\u002Fonc.2010.316",{"id":18,"text":1347,"url":18,"identifiers":3419},{"doi":1349},{"id":18,"text":1303,"url":18,"identifiers":3421},{"doi":1305},{"id":18,"text":3423,"url":18,"identifiers":3424},"Vos, 2006, RASSF family proteins and Ras transformation, Methods Enzymol, 407, 311, 10.1016\u002FS0076-6879(05)07026-6",{"doi":3425},"10.1016\u002FS0076-6879(05)07026-6",{"id":18,"text":3427,"url":18,"identifiers":3428},"Gordon, 2011, RASSF1A: not a prototypical Ras effector, Small GTPases, 2, 148, 10.4161\u002Fsgtp.2.3.16286",{"doi":3429},"10.4161\u002Fsgtp.2.3.16286",{"id":18,"text":3431,"url":18,"identifiers":3432},"Lee, 2014, XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313, Proc Natl Acad Sci U S A, 111, 15532, 10.1073\u002Fpnas.1411746111",{"doi":3433},"10.1073\u002Fpnas.1411746111",{"id":18,"text":3435,"url":18,"identifiers":3436},"Han, 2013, ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21WAF1, Cell Death Differ, 20, 1055, 10.1038\u002Fcdd.2013.33",{"doi":3437},"10.1038\u002Fcdd.2013.33",{"id":18,"text":3439,"url":18,"identifiers":3440},"Yoshizaki, 2003, Activity of Rho-family GTPases during cell division as visualized with FRET-based probes, J Cell Biol, 162, 223, 10.1083\u002Fjcb.200212049",{"doi":3441},"10.1083\u002Fjcb.200212049",{"id":18,"text":3443,"url":18,"identifiers":3444},"Rossman, 2005, GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors, Nat Rev Mol Cell Biol, 6, 167, 10.1038\u002Fnrm1587",{"doi":3445},"10.1038\u002Fnrm1587",{"id":18,"text":3447,"url":18,"identifiers":3448},"Sahai, 2007, Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility, J Cell Biol, 176, 35, 10.1083\u002Fjcb.200605135",{"doi":3449},"10.1083\u002Fjcb.200605135",{"id":18,"text":3451,"url":18,"identifiers":3452},"Blumenstein, 2004, Models of the cooperative mechanism for Rho effector recognition: implications for RhoA-mediated effector activation, J Biol Chem, 279, 53419, 10.1074\u002Fjbc.M409551200",{"doi":3453},"10.1074\u002Fjbc.M409551200",{"id":18,"text":3455,"url":18,"identifiers":3456},"Chen, 2013, Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells, Oncogene, 32, 3754, 10.1038\u002Fonc.2012.383",{"doi":3457},"10.1038\u002Fonc.2012.383",{"id":18,"text":3459,"url":18,"identifiers":3460},"Park, 2010, Tumor suppressor ras association domain family 5 (RASSF5\u002FNORE1) mediates death receptor ligand-induced apoptosis, J Biol Chem, 285, 35029, 10.1074\u002Fjbc.M110.165506",{"doi":3461},"10.1074\u002Fjbc.M110.165506",{"id":18,"text":3463,"url":18,"identifiers":3464},"Ikeda, 2007, Ras-association domain family protein 6 induces apoptosis via both caspase-dependent and caspase-independent pathways, Exp Cell Res, 313, 1484, 10.1016\u002Fj.yexcr.2007.02.013",{"doi":3465},"10.1016\u002Fj.yexcr.2007.02.013",{"id":18,"text":1307,"url":18,"identifiers":3467},{"doi":1309},{"id":18,"text":3469,"url":18,"identifiers":3470},"Stieglitz, 2008, Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II, EMBO J, 27, 1995, 10.1038\u002Femboj.2008.125",{"doi":3471},"10.1038\u002Femboj.2008.125",{"id":18,"text":3473,"url":18,"identifiers":3474},"Harjes, 2006, GTP-Ras disrupts the intramolecular complex of C1 and RA domains of Nore1, Structure, 14, 881, 10.1016\u002Fj.str.2006.03.008",{"doi":3475},"10.1016\u002Fj.str.2006.03.008",{"id":18,"text":3477,"url":18,"identifiers":3478},"Shibata, 1996, Characterization of the interaction between RhoA and the amino-terminal region of PKN, FEBS Lett, 385, 221, 10.1016\u002F0014-5793(96)00385-7",{"doi":3479},"10.1016\u002F0014-5793(96)00385-7",{"id":18,"text":3481,"url":18,"identifiers":3482},"Ihara, 1998, Crystal structure of human RhoA in a dominantly active form complexed with a GTP analogue, J Biol Chem, 273, 9656, 10.1074\u002Fjbc.273.16.9656",{"doi":3483},"10.1074\u002Fjbc.273.16.9656",{"id":18,"text":3485,"url":18,"identifiers":3486},"Timpson, 2011, Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53, Cancer Res, 71, 747, 10.1158\u002F0008-5472.CAN-10-2267",{"doi":3487},"10.1158\u002F0008-5472.CAN-10-2267",{"id":18,"text":3489,"url":18,"identifiers":3490},"Dallol, 2005, Involvement of the RASSF1A tumor suppressor gene in controlling cell migration, Cancer Res, 65, 7653, 10.1158\u002F0008-5472.CAN-05-0247",{"doi":3491},"10.1158\u002F0008-5472.CAN-05-0247",{"id":18,"text":3493,"url":18,"identifiers":3494},"Bhowmick, 2001, Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism, Mol Biol Cell, 12, 27, 10.1091\u002Fmbc.12.1.27",{"doi":3495},"10.1091\u002Fmbc.12.1.27",{"id":3497,"createTime":3498,"updateTime":3498,"relativeEntities":3499,"slug":3500,"properties":3501,"entityType":46,"verifyStatus":47,"verifyTime":3517,"verifyNote":49,"syncStatus":17,"languages":3518,"translateLanguages":18,"viewCount":19,"primaryUrl":3519,"fullTextUrl":18,"authors":3520,"publicationType":111,"publisherRelationship":3650,"citationCount":3664,"citationInfo":3665,"publishDate":3667,"publishYear":1973,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":18,"openAccess":18,"references":3668,"isForceReanalyzing":344},"9f8f623e-b76d-4fd3-a828-9218cbe0c057","2024-12-14T16:48:20.440+00:00",[],"Chemotherapy-Induces-Tumor-Clearance-Independent-of-Apoptosis",{"mag":3502,"keywords":3504,"pmc":3505,"openalex":3507,"abstract":3509,"title":3511,"pm":3513,"doi":3515},{"VOID":3503},"2120909020",{},{"VOID":3506},"2596650",{"VOID":3508},"W2120909020",{"EN":3510},"\u003Cjats:title>Abstract\u003C\u002Fjats:title>\n               \u003Cjats:p>Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. The ultimate goal of cancer treatment is to selectively induce cancer cell death and overcome drug resistance. A deeper understanding of how a given chemotherapy affects tumor cell death is needed to develop strategically designed anticancer agents. Here, we use a xenograft mouse tumor system generated from genetically defined cells deficient in apoptosis to examine the involvement of multiple forms of cell death induced by cyclophosphamide (CP), a DNA alkylating agent commonly used in chemotherapy. We find that although apoptosis facilitates tumor regression, it is dispensable for complete tumor regression as other forms of cell death are activated. Sporadic necrosis is observed in both apoptosis-competent and deficient tumors evident by tumor cell morphology, extracellular release of high mobility group box 1 protein, and activation of innate immune cells in CP-treated tumors. Our findings indicate that in apoptosis-deficient tumors, necrosis may play a fundamental role in tumor clearance by stimulating the innate immune response. [Cancer Res 2008;68(23):9595–600]\u003C\u002Fjats:p>",{"EN":3512},"Chemotherapy Induces Tumor Clearance Independent of Apoptosis",{"VOID":3514},"19047135",{"VOID":3516},"10.1158\u002F0008-5472.can-08-2452","2024-12-14T16:48:20.439+00:00",[51],"https:\u002F\u002Faacrjournals.org\u002Fcancerres\u002Farticle\u002F68\u002F23\u002F9595\u002F540598\u002FChemotherapy-Induces-Tumor-Clearance-Independent",[3521,3540,3561,3580,3597,3627],{"id":3522,"sortIndex":19,"researcher":18,"roles":3523,"affiliations":3524,"properties":3535},"9bcdd75d-51d2-4e60-bfb7-84e871dce84d",[],[3525],{"id":3526,"sortIndex":19,"affiliation":3527,"properties":18},"fda7d972-79e7-404d-ac0d-e3b3ca452040",{"id":3528,"createTime":3529,"updateTime":3529,"relativeEntities":3530,"slug":3531,"properties":3532,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"cfb782c7-43ba-4e2d-8307-2f7438413e8b","2024-12-14T16:48:20.457+00:00",[],"Graduate-Program-in-Molecular-and-Cellular-Biology-Department-of-Molecular-Genetics-Stony-Brook-University-Stony-Brook-New-York-11794-5222-USA-",{"title":3533},{"EN":3534},"Graduate Program in Molecular and Cellular Biology, Department of Molecular Genetics, Stony Brook University, Stony Brook, New York 11794-5222, USA.",{"openalex":3536,"title":3538},{"VOID":3537},"A5108281148",{"EN":3539},"Jennifer L. Guerriero",{"id":3541,"sortIndex":134,"researcher":18,"roles":3542,"affiliations":3543,"properties":3554},"d5f58516-f4c1-4af8-81e0-39baf07ff203",[],[3544],{"id":3545,"sortIndex":19,"affiliation":3546,"properties":18},"35c773e1-6d53-4e61-866b-5873c8e2be86",{"id":3547,"createTime":3548,"updateTime":3548,"relativeEntities":3549,"slug":3550,"properties":3551,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"57e3a1a9-a839-48c5-9a3b-e2972f129bd2","2024-12-14T16:48:20.546+00:00",[],"3Pharmacological-Sciences-Stony-Brook-University-Stony-Brook-New-York-and",{"title":3552},{"EN":3553},"3Pharmacological Sciences, Stony Brook University, Stony Brook, New York; and",{"openalex":3555,"orcid":3557,"title":3559},{"VOID":3556},"A5054373028",{"VOID":3558},"https:\u002F\u002Forcid.org\u002F0000-0001-9360-3019",{"EN":3560},"Howard C. Crawford",{"id":3562,"sortIndex":135,"researcher":18,"roles":3563,"affiliations":3564,"properties":3575},"544bda26-2045-4f4d-9a22-f6eb121ea77c",[],[3565],{"id":3566,"sortIndex":19,"affiliation":3567,"properties":18},"b798edac-8a66-405f-a910-7f25a04ee0a6",{"id":3568,"createTime":3569,"updateTime":3569,"relativeEntities":3570,"slug":3571,"properties":3572,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"a3560c7c-161b-4178-9150-36b761e67473","2024-12-14T16:48:20.478+00:00",[],"4Abramson-Family-Cancer-Research-Institute-Department-of-Cancer-Biology-University-of-Pennsylvania-Philadelphia-Pennsylvania",{"title":3573},{"EN":3574},"4Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania",{"openalex":3576,"title":3578},{"VOID":3577},"A5112730469",{"EN":3579},"Fangping Zhao",{"id":3581,"sortIndex":97,"researcher":18,"roles":3582,"affiliations":3583,"properties":3590},"8bc5362a-8a5c-4951-960d-d9c4a2a2a628",[],[3584],{"id":3585,"sortIndex":19,"affiliation":3586,"properties":18},"c7853415-728c-4ae9-945e-fa6bd29606d6",{"id":3568,"createTime":3569,"updateTime":3569,"relativeEntities":3587,"slug":3571,"properties":3588,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":3589},{"EN":3574},{"openalex":3591,"orcid":3593,"title":3595},{"VOID":3592},"A5073794395",{"VOID":3594},"https:\u002F\u002Forcid.org\u002F0000-0002-1086-9426",{"EN":3596},"Dara Ditsworth",{"id":3598,"sortIndex":56,"researcher":18,"roles":3599,"affiliations":3600,"properties":3622},"b729f09a-ddb0-4704-927d-67e93d4c7e6e",[],[3601,3612],{"id":3602,"sortIndex":97,"affiliation":3603,"properties":18},"a66bc149-adfc-4daa-8eb2-b3f131b1902b",{"id":3604,"createTime":3605,"updateTime":3606,"relativeEntities":3607,"slug":3608,"properties":3609,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"21e4135d-cbef-44dd-863d-b0bacc603d5e","2024-04-13T11:26:30.857+00:00","2024-12-20T10:06:06.183+00:00",[],"Stony-Brook-University",{"title":3610},{"EN":3611},"Stony Brook University",{"id":3613,"sortIndex":19,"affiliation":3614,"properties":18},"346bf511-ebb9-469d-bac5-2ddf9a97847f",{"id":3615,"createTime":3616,"updateTime":3616,"relativeEntities":3617,"slug":3618,"properties":3619,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},"3a70a71e-5925-4c1d-9ca7-468e5a0b3278","2024-12-14T16:48:20.500+00:00",[],"2Molecular-Genetics-and-Microbiology-and",{"title":3620},{"EN":3621},"2Molecular Genetics and Microbiology and",{"openalex":3623,"title":3625},{"VOID":3624},"A5111936768",{"EN":3626},"Yongjun Fan",{"id":3628,"sortIndex":131,"researcher":18,"roles":3629,"affiliations":3630,"properties":3643},"346951a9-49c7-429d-ad54-3951d1561437",[],[3631,3637],{"id":3632,"sortIndex":19,"affiliation":3633,"properties":18},"3272dcbe-6777-4681-aa4f-c1218276f19f",{"id":3615,"createTime":3616,"updateTime":3616,"relativeEntities":3634,"slug":3618,"properties":3635,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":3636},{"EN":3621},{"id":3638,"sortIndex":97,"affiliation":3639,"properties":18},"f334eaf8-8509-4b64-a4e9-3af6f593272d",{"id":3604,"createTime":3605,"updateTime":3606,"relativeEntities":3640,"slug":3608,"properties":3641,"entityType":70,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19},[],{"title":3642},{"EN":3611},{"openalex":3644,"orcid":3646,"title":3648},{"VOID":3645},"A5091798101",{"VOID":3647},"https:\u002F\u002Forcid.org\u002F0000-0002-3129-8220",{"EN":3649},"Wei‐Xing Zong",{"url":18,"publisher":3651,"properties":3659},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":3652,"slug":10,"properties":3653,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"syncStatus":17,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":3656,"manageAffiliations":3657,"indexDatabases":3658,"url":18,"thumbnailPath":18,"statistic":18,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"eissn":3654,"title":3655},{"VOID":13},{"EN":15},[],[],[],{"volume":3660,"pages":3661,"issue":3663},{"VOID":1964},{"VOID":3662},"9595-9600",{"VOID":913},56,{"total":3664,"publishYear":18,"statisticByYear":3666},{"2012":136,"2013":135,"2014":137,"2015":138,"2016":56,"2017":134,"2018":97,"2019":56,"2020":131,"2021":56,"2022":97,"2023":56,"2024":56},"2008-12-01",[3669,3673,3677,3681,3684,3688,3692,3696,3700,3704,3707,3711,3715,3719,3723,3727,3731],{"id":18,"text":3670,"url":18,"identifiers":3671},"Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.",{"doi":3672},"10.1016\u002FS0092-8674(00)81683-9",{"id":18,"text":3674,"url":18,"identifiers":3675},"Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 2004; 4: 592–603.",{"doi":3676},"10.1038\u002Fnrc1412",{"id":18,"text":3678,"url":18,"identifiers":3679},"Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26: 1324–37.",{"doi":3680},"10.1038\u002Fsj.onc.1210220",{"id":18,"text":3682,"url":18,"identifiers":3683},"Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy. Principles and Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.",{},{"id":18,"text":3685,"url":18,"identifiers":3686},"Brown JM, Attardi LD. The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 2005; 5: 231–7.",{"doi":3687},"10.1038\u002Fnrc1560",{"id":18,"text":3689,"url":18,"identifiers":3690},"Melino G, Knight RA, Nicotera P. How many ways to die? How many different models of cell death? Cell Death Differ 2005; 12 Suppl 2: 1457–62.",{"doi":3691},"10.1038\u002Fsj.cdd.4401781",{"id":18,"text":3693,"url":18,"identifiers":3694},"Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007; 7: 961–7.",{"doi":3695},"10.1038\u002Fnrc2254",{"id":18,"text":3697,"url":18,"identifiers":3698},"Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292: 727–30.",{"doi":3699},"10.1126\u002Fscience.1059108",{"id":18,"text":3701,"url":18,"identifiers":3702},"Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004; 23: 2825–37.",{"doi":3703},"10.1038\u002Fsj.onc.1207528",{"id":18,"text":3705,"url":18,"identifiers":3706},"Rhodin JAG. Histology. A Text and Atlas. New York (NY): Oxford University Press; 1974. p. 371–98.",{},{"id":18,"text":3708,"url":18,"identifiers":3709},"Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191–5.",{"doi":3710},"10.1038\u002Fnature00858",{"id":18,"text":3712,"url":18,"identifiers":3713},"Kwon CH, Borch RF, Engel J, Niemeyer U. Activation mechanisms of mafosfamide and the role of thiols in cyclophosphamide metabolism. J Med Chem 1987; 30: 395–9.",{"doi":3714},"10.1021\u002Fjm00385a023",{"id":18,"text":3716,"url":18,"identifiers":3717},"Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine\u002Fparacrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest 1998; 101: 890–8.",{"doi":3718},"10.1172\u002FJCI1112",{"id":18,"text":3720,"url":18,"identifiers":3721},"Zeh HJ III, Lotze MT. Addicted to death: invasive cancer and the immune response to unscheduled cell death. J Immunother 2005; 28: 1–9.",{"doi":3722},"10.1097\u002F00002371-200501000-00001",{"id":18,"text":3724,"url":18,"identifiers":3725},"Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol 1992; 52: 296–302.",{"doi":3726},"10.1002\u002Fjlb.52.3.296",{"id":18,"text":3728,"url":18,"identifiers":3729},"Mizgerd JP, Molina RM, Stearns RC, Brain JD, Warner AE. Gadolinium induces macrophage apoptosis. J Leukoc Biol 1996; 59: 189–95.",{"doi":3730},"10.1002\u002Fjlb.59.2.189",{"id":18,"text":3732,"url":18,"identifiers":3733},"Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 2004; 4: 641–8.",{"doi":3734},"10.1038\u002Fnri1415"]