Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis

Wang, 2014, Roles of F-box proteins in cancer, Nat. Rev. Cancer, 14, 233, 10.1038/nrc3700 Skaar, 2014, SCF ubiquitin ligase-targeted therapies, Nat. Rev. Drug Discov., 13, 889, 10.1038/nrd4432 Kornitzer, 2000, Modes of regulation of ubiquitin-mediated protein degradation, J. Cell. Physiol., 182, 1, 10.1002/(SICI)1097-4652(200001)182:1<1::AID-JCP1>3.0.CO;2-V Glickman, 2002, The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction, Physiol. Rev., 82, 373, 10.1152/physrev.00027.2001 Ciechanover, 2002, Ubiquitin-mediated degradation of cellular proteins in health and disease, Hepatology, 35, 3, 10.1053/jhep.2002.30316 Amir, 2001, The ubiquitin-proteasome system: the relationship between protein degradation and human diseases, Harefuah, 140, 1172 Teixeira, 2013, Ubiquitin ligases and cell cycle control, Annu. Rev. Biochem., 82, 387, 10.1146/annurev-biochem-060410-105307 Groll, 2003, Substrate access and processing by the 20S proteasome core particle, Int. J. Biochem. Cell Biol., 35, 606, 10.1016/S1357-2725(02)00390-4 Yang, 2010, Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development, Oncogene, 29, 4493, 10.1038/onc.2010.190 Behrends, 2011, Constructing and decoding unconventional ubiquitin chains, Nat. Struct. Mol. Biol., 18, 520, 10.1038/nsmb.2066 Li, 2008, Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling, PLoS ONE, 3, e1487, 10.1371/journal.pone.0001487 Deshaies, 2009, RING domain E3 ubiquitin ligases, Annu. Rev. Biochem., 78, 399, 10.1146/annurev.biochem.78.101807.093809 Petroski, 2005, Function and regulation of cullin-RING ubiquitin ligases, Nat. Rev. Mol. Cell Biol., 6, 9, 10.1038/nrm1547 Hotton, 2008, Regulation of cullin RING ligases, Annu. Rev. Plant Biol., 59, 467, 10.1146/annurev.arplant.58.032806.104011 Bosu, 2008, Cullin-RING ubiquitin ligases: global regulation and activation cycles, Cell Div., 3, 7, 10.1186/1747-1028-3-7 Chen, 2015, Cullin family proteins and tumorigenesis: genetic association and molecular mechanisms, J. Cancer, 6, 233, 10.7150/jca.11076 Lydeard, 2013, Building and remodelling Cullin-RING E3 ubiquitin ligases, EMBO Rep., 14, 1050, 10.1038/embor.2013.173 Sarikas, 2011, The cullin protein family, Genome Biol., 12, 220, 10.1186/gb-2011-12-4-220 Duda, 2011, Structural regulation of cullin-RING ubiquitin ligase complexes, Curr. Opin. Struct. Biol., 21, 257, 10.1016/j.sbi.2011.01.003 Hua, 2011, The cullin-RING ubiquitin-protein ligases, Annu. Rev. Plant Biol., 62, 299, 10.1146/annurev-arplant-042809-112256 Lipkowitz, 2011, RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis, Nat. Rev. Cancer, 11, 629, 10.1038/nrc3120 Kipreos, 2000, The F-box protein family, Genome Biol., 1, 10.1186/gb-2000-1-5-reviews3002 Cardozo, 2004, The SCF ubiquitin ligase: insights into a molecular machine, Nat. Rev. Mol. Cell Biol., 5, 739, 10.1038/nrm1471 Skaar, 2013, Mechanisms and function of substrate recruitment by F-box proteins, Nat. Rev. Mol. Cell Biol., 14, 369, 10.1038/nrm3582 Signoretti, 2002, Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer, J. Clin. Invest., 110, 633, 10.1172/JCI0215795 Gstaiger, 2001, Skp2 is oncogenic and overexpressed in human cancers, Proc. Natl. Acad. Sci. U. S. A., 98, 5043, 10.1073/pnas.081474898 Yokoi, 2004, Amplification and overexpression of SKP2 are associated with metastasis of non-small-cell lung cancers to lymph nodes, Am. J. Pathol., 165, 175, 10.1016/S0002-9440(10)63286-5 Shim, 2003, Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate, Cancer Res., 63, 1583 Latres, 2001, Role of the F-box protein Skp2 in lymphomagenesis, Proc. Natl. Acad. Sci. U. S. A., 98, 2515, 10.1073/pnas.041475098 Umanskaya, 2007, Skp2B stimulates mammary gland development by inhibiting REA, the repressor of the estrogen receptor, Mol. Cell. Biol., 27, 7615, 10.1128/MCB.01239-07 Wang, 2010, Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/− mice, Nat. Genet., 42, 83, 10.1038/ng.498 Chan, 2012, The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis, Cell, 149, 1098, 10.1016/j.cell.2012.02.065 Lin, 2010, Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence, Nature, 464, 374, 10.1038/nature08815 Sistrunk, 2013, Skp2 deficiency inhibits chemical skin tumorigenesis independent of p27(Kip1) accumulation, Am. J. Pathol., 182, 1854, 10.1016/j.ajpath.2013.01.016 Zhao, 2013, Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors, Cancer Cell, 24, 645, 10.1016/j.ccr.2013.09.021 Carrano, 1999, SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27, Nat. Cell Biol., 1, 193, 10.1038/12013 Sutterluty, 1999, p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells, Nat. Cell Biol., 1, 207, 10.1038/12027 Nakayama, 2000, Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication, EMBO J., 19, 2069, 10.1093/emboj/19.9.2069 Bornstein, 2003, Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase, J. Biol. Chem., 278, 25752, 10.1074/jbc.M301774200 Yu, 1998, Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins, Proc. Natl. Acad. Sci. U. S. A., 95, 11324, 10.1073/pnas.95.19.11324 Kamura, 2003, Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation, Proc. Natl. Acad. Sci. U. S. A., 100, 10231, 10.1073/pnas.1831009100 Tedesco, 2002, The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2), Genes Dev., 16, 2946, 10.1101/gad.1011202 Zhang, 1995, p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase, Cell, 82, 915, 10.1016/0092-8674(95)90271-6 Marti, 1999, Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation, Nat. Cell Biol., 1, 14, 10.1038/8984 Mendez, 2002, Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication, Mol. Cell, 9, 481, 10.1016/S1097-2765(02)00467-7 Li, 2003, The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation, J. Biol. Chem., 278, 30854, 10.1074/jbc.C300251200 Kiernan, 2001, Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome, Mol. Cell. Biol., 21, 7956, 10.1128/MCB.21.23.7956-7970.2001 von der Lehr, 2003, The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription, Mol. Cell, 11, 1189, 10.1016/S1097-2765(03)00193-X Hiramatsu, 2006, Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination, Cancer Res., 66, 8477, 10.1158/0008-5472.CAN-06-1603 Song, 2008, Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1-S transition, Oncogene, 27, 3176, 10.1038/sj.onc.1210971 Liang, 2004, Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2, Mol. Cell. Biol., 24, 7524, 10.1128/MCB.24.17.7524-7537.2004 Jiang, 2005, Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle, Mol. Cell, 18, 699, 10.1016/j.molcel.2005.05.011 Tokarz, 2004, The ISG15 isopeptidase UBP43 is regulated by proteolysis via the SCFSkp2 ubiquitin ligase, J. Biol. Chem., 279, 46424, 10.1074/jbc.M403189200 Huang, 2005, Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation, Proc. Natl. Acad. Sci. U. S. A., 102, 1649, 10.1073/pnas.0406789102 Parameswaran, 2015, Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection, Cell Cycle, 14, 437, 10.4161/15384101.2014.972901 Moro, 2006, Up-regulation of Skp2 after prostate cancer cell adhesion to basement membranes results in BRCA2 degradation and cell proliferation, J. Biol. Chem., 281, 22100, 10.1074/jbc.M604636200 Jamal, 2015, The G1 phase E3 ubiquitin ligase TRUSS that gets deregulated in human cancers is a novel substrate of the S-phase E3 ubiquitin ligase Skp2, Cell Cycle, 14, 2688, 10.1080/15384101.2015.1056946 Xu, 2015, Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis, Nat. Commun., 6, 6641, 10.1038/ncomms7641 Di Giorgio, 2015, The control operated by the cell cycle machinery on MEF2 stability contributes to the downregulation of CDKN1A and entry into S phase, Mol. Cell. Biol., 35, 1633, 10.1128/MCB.01461-14 Ougolkov, 2004, Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer, J. Natl. Cancer Inst., 96, 1161, 10.1093/jnci/djh219 Muerkoster, 2005, Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells, Cancer Res., 65, 1316, 10.1158/0008-5472.CAN-04-1626 Koch, 2005, Elevated expression of Wnt antagonists is a common event in hepatoblastomas, Clin. Cancer Res., 11, 4295, 10.1158/1078-0432.CCR-04-1162 Fuchs, 2004, The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer, Oncogene, 23, 2028, 10.1038/sj.onc.1207389 Saitoh, 2001, Expression profiles of betaTRCP1 and betaTRCP2, and mutation analysis of betaTRCP2 in gastric cancer, Int. J. Oncol., 18, 959 Kim, 2007, Somatic mutations of the beta-TrCP gene in gastric cancer, APMIS, 115, 127, 10.1111/j.1600-0463.2007.apm_562.x Kudo, 2004, Role of F-box protein betaTrcp1 in mammary gland development and tumorigenesis, Mol. Cell. Biol., 24, 8184, 10.1128/MCB.24.18.8184-8194.2004 Bhatia, 2011, Role of beta-TrCP ubiquitin ligase receptor in UVB mediated responses in skin, Arch. Biochem. Biophys., 508, 178, 10.1016/j.abb.2010.12.023 Guardavaccaro, 2003, Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo, Dev. Cell, 4, 799, 10.1016/S1534-5807(03)00154-0 Kanarek, 2010, Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCF{beta}-TrCP by single substrate depletion, Genes Dev., 24, 470, 10.1101/gad.551610 Busino, 2003, Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage, Nature, 426, 87, 10.1038/nature02082 Jin, 2003, SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase, Genes Dev., 17, 3062, 10.1101/gad.1157503 Liu, 1999, beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation, Proc. Natl. Acad. Sci. U. S. A., 96, 6273, 10.1073/pnas.96.11.6273 Zhou, 2004, Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition, Nat. Cell Biol., 6, 931, 10.1038/ncb1173 Pons, 2008, Transfer-NMR and docking studies identify the binding of the peptide derived from activating transcription factor 4 to protein ubiquitin ligase beta-TrCP, Competition STD-NMR with beta-catenin, Biochemistry, 47, 14, 10.1021/bi7014212 Ciechanover, 2001, Mechanisms of ubiquitin-mediated, limited processing of the NF-kappaB1 precursor protein p105, Biochimie, 83, 341, 10.1016/S0300-9084(01)01239-1 Inuzuka, 2010, Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase, Cancer Cell, 18, 147, 10.1016/j.ccr.2010.06.015 Liu, 2015, Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair, Mol. Cell, 57, 648, 10.1016/j.molcel.2015.01.005 Tan, 1999, Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha, Mol. Cell, 3, 527, 10.1016/S1097-2765(00)80481-5 Tan, 2006, SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection, Neoplasia, 8, 1042, 10.1593/neo.06568 Dorrello, 2006, S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth, Science, 314, 467, 10.1126/science.1130276 Amir, 2004, Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase, Oncogene, 23, 2540, 10.1038/sj.onc.1207366 Wang, 2012, DEPTOR ubiquitination and destruction by SCF(beta-TrCP), Am. J. Physiol. Endocrinol. Metab., 303, E163, 10.1152/ajpendo.00105.2012 Watanabe, 2004, M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP, Proc. Natl. Acad. Sci. U. S. A., 101, 4419, 10.1073/pnas.0307700101 Loveless, 2015, DNA damage regulates translation through beta-TRCP targeting of CReP, PLOS Genet., 11, e1005292, 10.1371/journal.pgen.1005292 Zhu, 2014, DNA damage induces the accumulation of Tiam1 by blocking beta-TrCP-dependent degradation, J. Biol. Chem., 289, 15482, 10.1074/jbc.M114.553388 Yan, 2015, SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer, Genes Dev., 29, 672, 10.1101/gad.254292.114 Sun, 2009, JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation, Proc. Natl. Acad. Sci. U. S. A., 106, 10195, 10.1073/pnas.0901864106 Gutgemann, 2008, Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma, Mod. Pathol., 21, 445, 10.1038/modpathol.3801022 Min, 2013, Gynecologic Pathology Study Group of the Korean Society of, Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3, Int. J. Gynecol. Pathol., 32, 3, 10.1097/PGP.0b013e31825554e9 Lehman, 2007, Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors, Am. J. Pathol., 170, 1793, 10.2353/ajpath.2007.060767 Lee, 2006, Mouse emi1 has an essential function in mitotic progression during early embryogenesis, Mol. Cell. Biol., 26, 5373, 10.1128/MCB.00043-06 Reimann, 2001, Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex, Cell, 105, 645, 10.1016/S0092-8674(01)00361-0 Lu, 2012, The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation, J. Biol. Chem., 287, 41014, 10.1074/jbc.M112.407106 Sjögren, 2015, FBXO44-mediated degradation of RGS2 protein uniquely depends on a Cullin 4B/DDB1 complex, PLOS ONE, 10, e0123581, 10.1371/journal.pone.0123581 Fernandez-Saiz, 2013, SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma, Nat. Cell Biol., 15, 72, 10.1038/ncb2651 Cepeda, 2013, CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer, EMBO Mol. Med., 5, 999, 10.1002/emmm.201202341 Tzatsos, 2013, KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs, J. Clin. Invest., 123, 727 Wu, 2013, Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation, Mol. Cell, 49, 1134, 10.1016/j.molcel.2013.01.016 Laman, 2005, Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6, EMBO J., 24, 3104, 10.1038/sj.emboj.7600775 Lomonosov, 2011, Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis, PLoS ONE, 6, e21165, 10.1371/journal.pone.0021165 Meziane el, 2011, Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells, J. Cell Sci., 124, 2175, 10.1242/jcs.080465 Chang, 2006, The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein cIAP1 and promotes cIAP1 ubiquitination, Biochem. Biophys. Res. Commun., 342, 1022, 10.1016/j.bbrc.2006.02.061 Hsu, 2004, Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region, J. Biol. Chem., 279, 32592, 10.1074/jbc.M404950200 Bai, 1996, SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box, Cell, 86, 263, 10.1016/S0092-8674(00)80098-7 Yokoi, 2003, Down-regulation of SKP2 induces apoptosis in lung-cancer cells, Cancer Sci., 94, 344, 10.1111/j.1349-7006.2003.tb01444.x Shapira, 2005, The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma, Cancer, 103, 1336, 10.1002/cncr.20917 Nakayama, 2006, Ubiquitin ligases: cell-cycle control and cancer, Nat. Rev. Cancer, 6, 369, 10.1038/nrc1881 Hershko, 2008, Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer, Cancer, 112, 1415, 10.1002/cncr.23317 Mamillapalli, 2001, PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2), Curr. Biol., 11, 263, 10.1016/S0960-9822(01)00065-3 Abbas, 2013, Genomic instability in cancer, Cold Spring Harb. Perspect. Biol., 5, a012914, 10.1101/cshperspect.a012914 Nishitani, 2006, Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis, EMBO J., 25, 1126, 10.1038/sj.emboj.7601002 Liu, 2004, Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation, J. Biol. Chem., 279, 17283, 10.1074/jbc.C300549200 Takeda, 2005, Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase, J. Biol. Chem., 280, 23416, 10.1074/jbc.M501208200 Kim, 2003, Skp2 regulates Myc protein stability and activity, Mol. Cell, 11, 1177, 10.1016/S1097-2765(03)00173-4 Choi, 2010, Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells, Genes Dev., 24, 1236, 10.1101/gad.1920310 Evans, 2015, SKP2 is a direct transcriptional target of MYCN and a potential therapeutic target in neuroblastoma, Cancer Lett., 363, 37, 10.1016/j.canlet.2015.03.044 Bretones, 2011, SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells, J. Biol. Chem., 286, 9815, 10.1074/jbc.M110.165977 Gustafson, 2010, Myc proteins as therapeutic targets, Oncogene, 29, 1249, 10.1038/onc.2009.512 Buschbeck, 2009, The histone variant macroH2A is an epigenetic regulator of key developmental genes, Nat. Struct. Mol. Biol., 16, 1074, 10.1038/nsmb.1665 Zhang, 2005, Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA, Dev. Cell, 8, 19, 10.1016/j.devcel.2004.10.019 Davis, 2013, The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator, Genes Dev., 27, 151, 10.1101/gad.207720.112 Kapoor, 2010, The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature, 468, 1105, 10.1038/nature09590 Lu, 2014, Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity, Nat. Commun., 5, 3463, 10.1038/ncomms4463 Oh, 2004, The papillomavirus E7 oncoprotein is ubiquitinated by UbcH7 and Cullin 1- and Skp2-containing E3 ligase, J. Virol., 78, 5338, 10.1128/JVI.78.10.5338-5346.2004 Frescas, 2008, Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer, Nat. Rev. Cancer, 8, 438, 10.1038/nrc2396 Mark, 2014, Ubiquitin ligase trapping identifies an SCF(Saf1) pathway targeting unprocessed vacuolar/lysosomal proteins, Mol. Cell, 53, 148, 10.1016/j.molcel.2013.12.003 Kimball, 1999, Eukaryotic initiation factor eIF2, Int. J. Biochem. Cell Biol., 31, 25, 10.1016/S1357-2725(98)00128-9 Lehman, 2006, Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells, Cell Cycle, 5, 1569, 10.4161/cc.5.14.2925 Chen, 2011, Bcr-Abl-induced tyrosine phosphorylation of Emi1 to stabilize Skp2 protein via inhibition of ubiquitination in chronic myeloid leukemia cells, J. Cell. Physiol., 226, 407, 10.1002/jcp.22346 Di Fiore, 2007, Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C, J. Cell Biol., 177, 425, 10.1083/jcb.200611166 Cao, 2006, Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells, Oncogene, 25, 3719, 10.1038/sj.onc.1209408 Fukuda, 2011, Fbxl10/Kdm2b deficiency accelerates neural progenitor cell death and leads to exencephaly, Mol. Cell. Neurosci., 46, 614, 10.1016/j.mcn.2011.01.001 Ge, 2011, F-box protein 10, an NF-kappaB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway, Cell Death Differ., 18, 1184, 10.1038/cdd.2010.185 Koyama-Nasu, 2007, The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun, Nat. Cell Biol., 9, 1074, 10.1038/ncb1628 Janzer, 2012, The H3K4me3 histone demethylase Fbxl10 is a regulator of chemokine expression, cellular morphology, and the metabolome of fibroblasts, J. Biol. Chem., 287, 30984, 10.1074/jbc.M112.341040 He, 2008, The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b), Nat. Struct. Mol. Biol., 15, 1169, 10.1038/nsmb.1499 Frescas, 2007, JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes, Nature, 450, 309, 10.1038/nature06255 Knuutila, 1999, DNA copy number losses in human neoplasms, Am. J. Pathol., 155, 683, 10.1016/S0002-9440(10)65166-8 Davis, 2014, Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities, Cancer Cell, 26, 455, 10.1016/j.ccell.2014.09.013 Malyukova, 2007, The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling, Cancer Res., 67, 5611, 10.1158/0008-5472.CAN-06-4381 Maser, 2007, Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers, Nature, 447, 966, 10.1038/nature05886 O’Neil, 2007, FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors, J. Exp. Med., 204, 1813, 10.1084/jem.20070876 Thompson, 2007, The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia, J. Exp. Med., 204, 1825, 10.1084/jem.20070872 Hao, 2007, Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases, Mol. Cell, 26, 131, 10.1016/j.molcel.2007.02.022 Orlicky, 2003, Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase, Cell, 112, 243, 10.1016/S0092-8674(03)00034-5 Tang, 2007, Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination, Cell, 129, 1165, 10.1016/j.cell.2007.04.042 King, 2013, The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability, Cell, 153, 1552, 10.1016/j.cell.2013.05.041 Davis, 2014, Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines, Gut, 63, 792, 10.1136/gutjnl-2013-304719 Bonetti, 2008, Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma, J. Cell Biol., 182, 19, 10.1083/jcb.200711040 Grim, 2008, Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase, J. Cell Biol., 181, 913, 10.1083/jcb.200802076 Welcker, 2004, A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size, Curr. Biol., 14, 1852, 10.1016/j.cub.2004.09.083 Welcker, 2004, The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation, Proc. Natl. Acad. Sci. U. S. A., 101, 9085, 10.1073/pnas.0402770101 Yada, 2004, Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7, EMBO J., 23, 2116, 10.1038/sj.emboj.7600217 Agrawal, 2011, Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1, Science, 333, 1154, 10.1126/science.1206923 Le Gallo, 2012, Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes, Nat. Genet., 44, 1310, 10.1038/ng.2455 Mao, 2004, Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene, Nature, 432, 775, 10.1038/nature03155 Kwon, 2012, Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development, Mol. Cancer Res., 10, 834, 10.1158/1541-7786.MCR-12-0025 Matsuoka, 2008, Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL, Genes Dev., 22, 986, 10.1101/gad.1621808 Onoyama, 2007, Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis, J. Exp. Med., 204, 2875, 10.1084/jem.20062299 Thompson, 2008, Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7, J. Exp. Med., 205, 1395, 10.1084/jem.20080277 Babaei-Jadidi, 2011, FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch. Jun, and DEK for degradation, J. Exp. Med., 208, 295, 10.1084/jem.20100830 Sancho, 2010, F-box and WD repeat domain-containing 7 regulates intestinal cell lineage commitment and is a haploinsufficient tumor suppressor, Gastroenterology, 139, 929, 10.1053/j.gastro.2010.05.078 Reavie, 2013, Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression, Cancer Cell, 23, 362, 10.1016/j.ccr.2013.01.025 Takeishi, 2013, Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence, Cancer Cell, 23, 347, 10.1016/j.ccr.2013.01.026 Koepp, 2001, Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase, Science, 294, 173, 10.1126/science.1065203 Wei, 2005, The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase, Cancer Cell, 8, 25, 10.1016/j.ccr.2005.06.005 Bengoechea-Alonso, 2010, Tumor suppressor Fbxw7 regulates TGFbeta signaling by targeting TGIF1 for degradation, Oncogene, 29, 5322, 10.1038/onc.2010.278 Wu, 2001, SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation, Mol. Cell. Biol., 21, 7403, 10.1128/MCB.21.21.7403-7415.2001 Inuzuka, 2011, SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction, Nature, 471, 104, 10.1038/nature09732 Liu, 2010, The Fbw7/human CDC4 tumor suppressor targets proproliferative factor KLF5 for ubiquitination and degradation through multiple phosphodegron motifs, J. Biol. Chem., 285, 18858, 10.1074/jbc.M109.099440 Giraldez, 2014, SCF(FBXW7alpha) modulates the intra-S-phase DNA-damage checkpoint by regulating Polo like kinase-1 stability, Oncotarget, 5, 4370, 10.18632/oncotarget.2021 Watanabe, 2012, FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis, J. Neurosci., 32, 3352, 10.1523/JNEUROSCI.5659-11.2012 Chen, 2013, Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis, Cell Death Dis., 4, e759, 10.1038/cddis.2013.271 Chen, 2012, F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation, Blood, 119, 3132, 10.1182/blood-2011-06-358911 Chen, 2012, F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest, Oncogene, 31, 2566, 10.1038/onc.2011.432 Kuchay, 2013, FBXL2- and PTPL1-mediated degradation of p110-free p85beta regulatory subunit controls the PI(3)K signalling cascade, Nat. Cell Biol., 15, 472, 10.1038/ncb2731 Lin, 2006, Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex, Mol. Cell, 24, 355, 10.1016/j.molcel.2006.09.007 Barbash, 2008, Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer, Cancer Cell, 14, 68, 10.1016/j.ccr.2008.05.017 Vaites, 2011, The Fbx4 tumor suppressor regulates cyclin D1 accumulation and prevents neoplastic transformation, Mol. Cell. Biol., 31, 4513, 10.1128/MCB.05733-11 Lian, 2015, FBXO4 loss facilitates carcinogen induced papilloma development in mice, Cancer Biol. Ther., 16, 750, 10.1080/15384047.2015.1026512 Kanie, 2012, Genetic reevaluation of the role of F-box proteins in cyclin D1 degradation, Mol. Cell. Biol., 32, 590, 10.1128/MCB.06570-11 Jia, 2009, F-box proteins FBXO31 and FBX4 in regulation of cyclin D1 degradation upon DNA damage, Pigment Cell Melanoma Res., 22, 518, 10.1111/j.1755-148X.2009.00611.x Lee, 2006, The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance, J. Biol. Chem., 281, 759, 10.1074/jbc.M509855200 Miller, 2003, Pooled analysis of loss of heterozygosity in breast cancer: a genome scan provides comparative evidence for multiple tumor suppressors and identifies novel candidate regions, Am. J. Hum. Genet., 73, 748, 10.1086/378522 Kumar, 2005, FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex, Cancer Res., 65, 11304, 10.1158/0008-5472.CAN-05-0936 Launonen, 2000, Loss of heterozygosity at chromosomes 3, 6, 8, 11, 16, and 17 in ovarian cancer: correlation to clinicopathological variables, Cancer Genet. Cytogenet., 122, 49, 10.1016/S0165-4608(00)00279-X Härkönen, 2005, Loss of heterozygosity in chromosomal region 16q24.3 associated with progression of prostate cancer, Prostate, 62, 267, 10.1002/pros.20147 Huang, 2010, FBXO31 is down-regulated and may function as a tumor suppressor in hepatocellular carcinoma, Oncol. Rep., 24, 715 Zhang, 2014, F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a, Oncotarget, 5, 6178, 10.18632/oncotarget.2183 Santra, 2009, F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage, Nature, 459, 722, 10.1038/nature08011 Johansson, 2014, SCF-FBXO31 E3 ligase targets DNA replication factor Cdt1 for proteolysis in the G2 phase of cell cycle to prevent re-replication, J. Biol. Chem., 289, 18514, 10.1074/jbc.M114.559930 Malonia, 2015, F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress, Proc. Natl. Acad. Sci. U. S. A., 112, 8632, 10.1073/pnas.1510929112 Vadhvani, 2013, The centrosomal E3 ubiquitin ligase FBXO31-SCF regulates neuronal morphogenesis and migration, PLOS ONE, 8, e57530, 10.1371/journal.pone.0057530 Kim, 2012, Pathway-based classification of cancer subtypes, Biol. Direct, 7, 21, 10.1186/1745-6150-7-21 Wang, 2010, Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers, Hum. Mol. Genet., 19, 2886, 10.1093/hmg/ddq174 Coon, 2012, Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A, causing mitotic arrest, Cell Cycle, 11, 721, 10.4161/cc.11.4.19171 Liu, 2015, The proapoptotic F-box Protein Fbxl7 regulates mitochondrial function by mediating the ubiquitylation and proteasomal degradation of survivin, J. Biol. Chem., 290, 11843, 10.1074/jbc.M114.629931 Vinas-Castells, 2010, The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation, J. Biol. Chem., 285, 3794, 10.1074/jbc.M109.065995 Vernon, 2006, Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa, Development, 133, 3359, 10.1242/dev.02504 Zheng, 2012, Essential role of Fbxl14 ubiquitin ligase in regulation of vertebrate axis formation through modulating Mkp3 level, Cell Res., 22, 936, 10.1038/cr.2012.37 Lander, 2011, The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1, J. Cell Biol., 194, 17, 10.1083/jcb.201012085 Zhu, 2012, Role of FBXL20 in human colorectal adenocarcinoma, Oncol. Rep., 28, 2290, 10.3892/or.2012.2065 Takagi, 2012, SCRAPPER regulates the thresholds of long-term potentiation/depression, the bidirectional synaptic plasticity in hippocampal CA3-CA1 synapses, Neural Plas., 2012, 352829 Yao, 2007, SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release, Cell, 130, 943, 10.1016/j.cell.2007.06.052 Xiao, 2015, FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation, Genes Dev., 29, 184, 10.1101/gad.252528.114 Wu, 2015, FBXL5 inhibits metastasis of gastric cancer through suppressing Snail1, Cell Physiol. Biochem., 35, 1764, 10.1159/000373988 Chen, 2014, FBXL5-mediated degradation of single-stranded DNA-binding protein hSSB1 controls DNA damage response, Nucleic Acids Res., 42, 11560, 10.1093/nar/gku876 Ruiz, 2013, F-box and leucine-rich repeat protein 5 (FBXL5) is required for maintenance of cellular and systemic iron homeostasis, J. Biol. Chem., 288, 552, 10.1074/jbc.M112.426171 Moroishi, 2011, The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo, Cell Metab., 14, 339, 10.1016/j.cmet.2011.07.011 Salahudeen, 2009, An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis, Science, 326, 722, 10.1126/science.1176326 Vashisht, 2009, Control of iron homeostasis by an iron-regulated ubiquitin ligase, Science, 326, 718, 10.1126/science.1176333 Zhang, 2007, FBXL5 interacts with p150Glued and regulates its ubiquitination, Biochem. Biophys. Res. Commun., 359, 34, 10.1016/j.bbrc.2007.05.068 Vinas-Castells, 2014, Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability, Nucleic Acids Res., 42, 1079, 10.1093/nar/gkt935 Tsutsumi, 2008, Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice, Mol. Cell. Biol., 28, 743, 10.1128/MCB.01665-07 Tsunematsu, 2006, Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development, Mol. Cell. Biol., 26, 6157, 10.1128/MCB.00595-06 Kim, 2012, mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8, Mol. Cell, 48, 875, 10.1016/j.molcel.2012.09.029 Kong, 2012, Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is mediated by CUL7 E3 ligase, PLoS ONE, 7, e46485, 10.1371/journal.pone.0046485 Okabe, 2006, A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation, PLoS ONE, 1, e128, 10.1371/journal.pone.0000128 Wang, 2014, The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1, J. Biol. Chem., 289, 4009, 10.1074/jbc.M113.520106 Fu, 2013, Low cyclin F expression in hepatocellular carcinoma associates with poor differentiation and unfavorable prognosis, Cancer Sci., 104, 508, 10.1111/cas.12100 Singhal, 2003, Alterations in cell cycle genes in early stage lung adenocarcinoma identified by expression profiling, Cancer Biol. Ther., 2, 291, 10.4161/cbt.2.3.399 Tetzlaff, 2004, Cyclin F disruption compromises placental development and affects normal cell cycle execution, Mol. Cell. Biol., 24, 2487, 10.1128/MCB.24.6.2487-2498.2004 D’Angiolella, 2010, SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation, Nature, 466, 138, 10.1038/nature09140 Emanuele, 2011, Global identification of modular cullin-RING ligase substrates, Cell, 147, 459, 10.1016/j.cell.2011.09.019 D’Angiolella, 2012, Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair, Cell, 149, 1023, 10.1016/j.cell.2012.03.043 Klein, 2015, Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control, Nat. Commun., 6, 5800, 10.1038/ncomms6800 Peschiaroli, 2009, The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73, Oncogene, 28, 3157, 10.1038/onc.2009.177 Chen, 2014, Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival, Cell Death Differ., 21, 1535, 10.1038/cdd.2014.92 Xu, 2015, Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors, Oncotarget, 6, 979, 10.18632/oncotarget.2825 Chiorazzi, 2013, Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma, Proc. Natl. Acad. Sci. U. S. A., 110, 3943, 10.1073/pnas.1217271110 Samuelson, 2007, Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk, Proc. Natl. Acad. Sci. U. S. A., 104, 6299, 10.1073/pnas.0701687104 Smits, 2012, An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a, Nucleic Acids Res., 40, 132, 10.1093/nar/gkr610 Duan, 2012, FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas, Nature, 481, 90, 10.1038/nature10688 Hardisty-Hughes, 2006, A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse, Hum. Mol. Genet., 15, 3273, 10.1093/hmg/ddl403 Abbas, 2013, CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration, Mol. Cell, 49, 1147, 10.1016/j.molcel.2013.02.003 Rossi, 2013, Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase, Mol. Cell, 49, 1159, 10.1016/j.molcel.2013.02.004 Abida, 2007, FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity, J. Biol. Chem., 282, 1797, 10.1074/jbc.M609001200 Zheng, 2014, PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis, Cancer Cell, 26, 358, 10.1016/j.ccr.2014.07.022 Jin, 2015, FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development, Cancer Lett., 362, 70, 10.1016/j.canlet.2015.03.037 Jeong, 2013, FBH1 protects melanocytes from transformation and is deregulated in melanomas, Cell Cycle (Georgetown, Tex.), 12, 1128, 10.4161/cc.24165 Zhang, 2014, Rare coding variants and breast cancer risk: evaluation of susceptibility Loci identified in genome-wide association studies, Cancer Epidemiol. Biomarkers Prev., 23, 622, 10.1158/1055-9965.EPI-13-1043 Laulier, 2010, Mammalian Fbh1 is important to restore normal mitotic progression following decatenation stress, DNA Repair, 9, 708, 10.1016/j.dnarep.2010.03.011 Lawrence, 2009, Stress-induced phosphorylation of S. pombe Atf1 abrogates its interaction with F box protein Fbh1, Curr. Biol., 19, 1907, 10.1016/j.cub.2009.09.044 Lockwood, 2013, The novel ubiquitin ligase complex, SCF(Fbxw4), interacts with the COP9 signalosome in an F-box dependent manner, is mutated, lost and under-expressed in human cancers, PLOS ONE, 8, e63610, 10.1371/journal.pone.0063610 Baumann, 2014, Disruption of the PRKCD–FBXO25–HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis, Nat. Med., 20, 1401, 10.1038/nm.3740 Jang, 2011, A novel Fbxo25 acts as an E3 ligase for destructing cardiac specific transcription factors, Biochem. Biophys. Res. Commun., 410, 183, 10.1016/j.bbrc.2011.05.011 Teixeira, 2013, The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein, J. Biol. Chem., 288, 28152, 10.1074/jbc.M113.504308 Gregory, 2003, Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization, J. Biol. Chem., 278, 51606, 10.1074/jbc.M310722200 Sears, 2000, Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability, Genes Dev., 14, 2501, 10.1101/gad.836800 Bahram, 2000, c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover, Blood, 95, 2104, 10.1182/blood.V95.6.2104 Bhatia, 1993, Point mutations in the c-Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas, Nat. Genet., 5, 56, 10.1038/ng0993-56 Weng, 2004, Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia, Science, 306, 269, 10.1126/science.1102160 Siu, 2014, Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7-mediated cyclin E regulation, Mol. Cell. Biol., 34, 3244, 10.1128/MCB.01528-13 Rajagopalan, 2004, Inactivation of hCDC4 can cause chromosomal instability, Nature, 428, 77, 10.1038/nature02313 Chen, 2011, FBXL2 is a ubiquitin E3 ligase subunit that triggers mitotic arrest, Cell Cycle, 10, 3487, 10.4161/cc.10.20.17742 Chen, 2013, A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation, Nat. Immunol., 14, 470, 10.1038/ni.2565 Li, 2010, Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase, J. Biol. Chem., 285, 13896, 10.1074/jbc.M110.111518 Barbash, 2011, Phosphorylation-dependent regulation of SCFFbx4 dimerization and activity involves a novel component 14-3-3, Oncogene, 30, 1995, 10.1038/onc.2010.584 Koo, 2014, Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth, Cancer Res., 74, 2555, 10.1158/0008-5472.CAN-13-2946 Pontano, 2008, Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability, Mol. Cell. Biol., 28, 7245, 10.1128/MCB.01085-08 Lee, 2013, The FBXO4 tumor suppressor functions as a barrier to BrafV600E-dependent metastatic melanoma, Mol. Cell. Biol., 33, 4422, 10.1128/MCB.00706-13 Abbas, 2011, CRL4Cdt2: master coordinator of cell cycle progression and genome stability, Cell Cycle, 10, 241, 10.4161/cc.10.2.14530 Abbas, 2010, CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation, Mol. Cell, 40, 9, 10.1016/j.molcel.2010.09.014 Chandrasekaran, 2011, Stress-stimulated mitogen-activated protein kinases control the stability and activity of the Cdt1 DNA replication licensing factor, Mol. Cell. Biol., 31, 4405, 10.1128/MCB.06163-11 Rizzardi, 2015, CDK1-dependent inhibition of the E3 ubiquitin ligase CRL4CDT2 ensures robust transition from S Phase to Mitosis, J. Biol. Chem., 290, 556, 10.1074/jbc.M114.614701 Abbas, 2013, Regulation of TGF-(signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2, Cell Cycle (Georgetown, Tex.), 12, 2175, 10.4161/cc.25314 Xu, 2008, The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation, Mol. Cell, 30, 403, 10.1016/j.molcel.2008.03.009 Lin, 2011, Fbxw8 is involved in the proliferation of human choriocarcinoma JEG-3 cells, Mol. Biol. Rep., 38, 1741, 10.1007/s11033-010-0288-7 Cen, 2014, FBXL5 targets cortactin for ubiquitination-mediated destruction to regulate gastric cancer cell migration, Tumour Biol., 35, 8633, 10.1007/s13277-014-2104-9 Dragoi, 2014, Novel strategies to enforce an epithelial phenotype in mesenchymal cells, Cancer Res., 74, 3659, 10.1158/0008-5472.CAN-13-3231 Hanahan, 2011, Hallmarks of cancer: the next generation, Cell, 144, 646, 10.1016/j.cell.2011.02.013 Fung, 2002, Cyclin F is degraded during G2-M by mechanisms fundamentally different from other cyclins, J. Biol. Chem., 277, 35140, 10.1074/jbc.M205503200 Li, 2013, USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110, Nature, 495, 255, 10.1038/nature11941 Martínez, 2009, Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice, Genes Dev., 23, 2060, 10.1101/gad.543509 Kim, 2004, SCFhFBH1 can act as helicase and E3 ubiquitin ligase, Nucleic Acids Res., 32, 2287, 10.1093/nar/gkh534 Fugger, 2009, Human Fbh1 helicase contributes to genome maintenance via pro- and anti-recombinase activities, J. Cell Biol., 186, 655, 10.1083/jcb.200812138 Jeong, 2013, FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress, J. Cell Biol., 200, 141, 10.1083/jcb.201209002 Fugger, 2013, FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress, Nat. Commun., 4, 1423, 10.1038/ncomms2395 Huen, 2010, BRCA1 and its toolbox for the maintenance of genome integrity, Nat. Rev. Mol. Cell Biol., 11, 138, 10.1038/nrm2831 Orlicky, 2010, An allosteric inhibitor of substrate recognition by the SCF(Cdc4) ubiquitin ligase, Nat. Biotechnol., 28, 733, 10.1038/nbt.1646 Aghajan, 2010, Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase, Nat. Biotechnol., 28, 738, 10.1038/nbt.1645 Wu, 2012, Specific small molecule inhibitors of Skp2-mediated p27 degradation, Chem. Biol., 19, 1515, 10.1016/j.chembiol.2012.09.015 Chan, 2013, Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression, Cell, 154, 556, 10.1016/j.cell.2013.06.048 Shuvalov, 2015, Current genome editing tools in gene therapy: new approaches to treat cancer, Curr. Gene Ther., 15, 511, 10.2174/1566523215666150818110241