CC3/TIP30 affects DNA damage repair
Tóm tắt
The pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. A number of studies support the notion that CC3 acts as a tumor and metastasis suppressor in various types of cancer. The yeast homolog of CC3 is likely to be involved in responses to DNA damage. Here we examined the potential role of CC3 in regulation of cellular responses to genotoxic stress.
We found that forced expression of CC3 in CC3-negative cells strongly delays the repair of UV-induced DNA damage. Exogenously introduced CC3 negatively affects expression levels of DDB2/XPE and p21CIP1, and inhibits induction of c-FOS after UV exposure. In addition, exogenous CC3 prevents the nuclear accumulation of P21CIP in response to UV. These changes in the levels/localization of relevant proteins resulting from the enforced expression of CC3 are likely to contribute to the observed delay in DNA damage repair. Silencing of CC3 in CC3-positive cells has a modest delaying effect on repair of the UV induced damage, but has a much more significant negative affect on the translesion DNA synthesis after UV exposure. This could be related to the higher expression levels and increased nuclear localization of p21CIP1 in cells where expression of CC3 is silenced. Expression of CC3 also inhibits repair of oxidative DNA damage and leads to a decrease in levels of nucleoredoxin, that could contribute to the reduced viability of CC3 expressing cells after oxidative insult.
Manipulation of the cellular levels of CC3 alters expression levels and/or subcellular localization of proteins that exhibit nucleocytoplasmic shuttling. This results in altered responses to genotoxic stress and adversely affects DNA damage repair by affecting the recruitment of adequate amounts of required proteins to proper cellular compartments. Excess of cellular CC3 has a significant negative effect on DNA repair after UV and oxidant exposure, while silencing of endogenous CC3 slightly delays repair of UV-induced damage.
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Tài liệu tham khảo
Shtivelman E: A link between metastasis and resistance to apoptosis of variant small cell lung carcinoma. Oncogene. 1997, 14: 2167-2173. 10.1038/sj.onc.1201059.
NicAmhlaoibh R, Shtivelman E: Metastasis suppressor CC3 inhibits angiogenic properties of tumor cells in vitro. Oncogene. 2001, 20: 270-275. 10.1038/sj.onc.1204075.
Whitman S, Wang X, Shalaby R, Shtivelman E: Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis. Mol Cell Biol. 2000, 20: 583-593. 10.1128/MCB.20.2.583-593.2000.
Zhao J, Ni H, Ma Y, Dong L, Dai J, Zhao F, Yan X, Lu B, Xu H, Guo Y: TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression. Hum Pathol. 2007, 38: 293-298. 10.1016/j.humpath.2006.08.005.
Li X, Zhang Y, Cao S, Chen X, Lu Y, Jin H, Sun S, Chen B, Liu J, Ding J: Reduction of TIP30 correlates with poor prognosis of gastric cancer patients and its restoration drastically inhibits tumor growth and metastasis. Int J Cancer. 2009, 124: 713-721. 10.1002/ijc.23967.
Lu B, Ma Y, Wu G, Tong X, Guo H, Liang A, Cong W, Liu C, Wang H, Wu M: Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma. Clin Cancer Res. 2008, 14: 7405-7412. 10.1158/1078-0432.CCR-08-0409.
Zhao J, Zhang X, Shi M, Xu H, Jin J, Ni H, Yang S, Dai J, Wu M, Guo Y: TIP30 inhibits growth of HCC cell lines and inhibits HCC xenografts in mice in combination with 5-FU. Hepatology. 2006, 44: 205-215. 10.1002/hep.21213.
Chen X, Cao X, Dong W, Luo S, Suo Z, Jin Y: Expression of TIP30 Tumor Suppressor Gene Is Down-Regulated in Human Colorectal Carcinoma. Dig Dis Sci. 2009
Tong X, Li K, Luo Z, Lu B, Liu X, Wang T, Pang M, Liang B, Tan M, Wu M: Decreased TIP30 expression promotes tumor metastasis in lung cancer. Am J Pathol. 2009, 174: 1931-1939. 10.2353/ajpath.2009.080846.
Liu Y, Thor A, Shtivelman E, Cao Y, Tu G, Heath TD, Debs RJ: Systemic gene delivery expands the repertoire of effective antiangiogenic agents. J Biol Chem. 1999, 274: 13338-13344. 10.1074/jbc.274.19.13338.
Xiao H, Palhan V, Yang Y, Roeder RG: TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes. Embo J. 2000, 19: 956-963. 10.1093/emboj/19.5.956.
Pecha J, Ankrapp D, Jiang C, Tang W, Hoshino I, Bruck K, Wagner KU, Xiao H: Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland. Oncogene. 2007, 26: 7423-7431. 10.1038/sj.onc.1210548.
Ito M, Jiang C, Krumm K, Zhang X, Pecha J, Zhao J, Guo Y, Roeder RG, Xiao H: TIP30 deficiency increases susceptibility to tumorigenesis. Cancer Res. 2003, 63: 8763-8767.
Zhang H, Zhang Y, Duan HO, Kirley SD, Lin SX, McDougal WS, Xiao H, Wu CL: TIP30 is associated with progression and metastasis of prostate cancer. Int J Cancer. 2008, 123: 810-816. 10.1002/ijc.23638.
Baker ME: TIP30, a cofactor for HIV-1 Tat-activated transcription, is homologous to short-chain dehydrogenases/reductases. Curr Biol. 1999, 9: R471-10.1016/S0960-9822(99)80297-8.
Baker ME, Yan L, Pear MR: Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression. Cell Mol Life Sci. 2000, 57: 851-858. 10.1007/s000180050047.
El Omari K, Bird LE, Nichols CE, Ren J, Stammers DK: Crystal structure of CC3 (TIP30): implications for its role as a tumor suppressor. J Biol Chem. 2005, 280: 18229-18236. 10.1074/jbc.M501113200.
King FW, Shtivelman E: Inhibition of nuclear import by the proapoptotic protein CC3. Mol Cell Biol. 2004, 24: 7091-7101. 10.1128/MCB.24.16.7091-7101.2004.
Nakahara J, Kanekura K, Nawa M, Aiso S, Suzuki N: Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis. J Clin Invest. 2009, 119: 169-181.
Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y: A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA. 2001, 98: 4569-4574. 10.1073/pnas.061034498.
Gasch AP, Huang M, Metzner S, Botstein D, Elledge SJ, Brown PO: Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p. Mol Biol Cell. 2001, 12: 2987-3003.
Lesur I, Campbell JL: The transcriptome of prematurely aging yeast cells is similar to that of telomerase-deficient cells. Mol Biol Cell. 2004, 15: 1297-1312. 10.1091/mbc.E03-10-0742.
Buscher M, Rahmsdorf HJ, Litfin M, Karin M, Herrlich P: Activation of the c-fos gene by UV and phorbol ester: different signal transduction pathways converge to the same enhancer element. Oncogene. 1988, 3: 301-311.
Christmann M, Tomicic MT, Aasland D, Kaina B: A role for UV-light-induced c-Fos: Stimulation of nucleotide excision repair and protection against sustained JNK activation and apoptosis. Carcinogenesis. 2007, 28: 183-190. 10.1093/carcin/bgl119.
Christmann M, Tomicic MT, Origer J, Aasland D, Kaina B: c-Fos is required for excision repair of UV-light induced DNA lesions by triggering the re-synthesis of XPF. Nucleic Acids Res. 2006, 34: 6530-6539. 10.1093/nar/gkl895.
Haas S, Kaina B: c-Fos is involved in the cellular defence against the genotoxic effect of UV radiation. Carcinogenesis. 1995, 16: 985-991. 10.1093/carcin/16.5.985.
Shiyanov P, Nag A, Raychaudhuri P: Cullin 4A associates with the UV-damaged DNA-binding protein DDB. J Biol Chem. 1999, 274: 35309-35312. 10.1074/jbc.274.50.35309.
Huang RP, Wu JX, Fan Y, Adamson ED: UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol. 1996, 133: 211-220. 10.1083/jcb.133.1.211.
Sukhatme VP, Cao XM, Chang LC, Tsai-Morris CH, Stamenkovich D, Ferreira PC, Cohen DR, Edwards SA, Shows TB, Curran T: A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988, 53: 37-43. 10.1016/0092-8674(88)90485-0.
Zhao J, Chen J, Lu B, Dong L, Wang H, Bi C, Wu G, Guo H, Wu M, Guo Y: TIP30 induces apoptosis under oxidative stress through stabilization of p53 messenger RNA in human hepatocellular carcinoma. Cancer Res. 2008, 68: 4133-4141. 10.1158/0008-5472.CAN-08-0432.
Stoyanova T, Yoon T, Kopanja D, Mokyr MB, Raychaudhuri P: The xeroderma pigmentosum group E gene product DDB2 activates nucleotide excision repair by regulating the level of p21Waf1/Cip1. Mol Cell Biol. 2008, 28: 177-187. 10.1128/MCB.00880-07.
Kurooka H, Kato K, Minoguchi S, Takahashi Y, Ikeda J, Habu S, Osawa N, Buchberg AM, Moriwaki K, Shisa H, Honjo T: Cloning and characterization of the nucleoredoxin gene that encodes a novel nuclear protein related to thioredoxin. Genomics. 1997, 39: 331-339. 10.1006/geno.1996.4493.
Funato Y, Michiue T, Asashima M, Miki H: The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol. 2006, 8: 501-508. 10.1038/ncb1405.
Wakasugi M, Kasashima H, Fukase Y, Imura M, Imai R, Yamada S, Cleaver JE, Matsunaga T: Physical and functional interaction between DDB and XPA in nucleotide excision repair. Nucleic Acids Res. 2009, 37: 516-525. 10.1093/nar/gkn964.
El-Mahdy MA, Zhu Q, Wang QE, Wani G, Praetorius-Ibba M, Wani AA: Cullin 4A-mediated proteolysis of DDB2 protein at DNA damage sites regulates in vivo lesion recognition by XPC. J Biol Chem. 2006, 281: 13404-13411. 10.1074/jbc.M511834200.
Kapetanaki MG, Guerrero-Santoro J, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS: The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites. Proc Natl Acad Sci USA. 2006, 103: 2588-2593. 10.1073/pnas.0511160103.
Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y: Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell. 2006, 22: 383-394. 10.1016/j.molcel.2006.03.035.
Liu L, Lee S, Zhang J, Peters SB, Hannah J, Zhang Y, Yin Y, Koff A, Ma L, Zhou P: CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis. Mol Cell. 2009, 34: 451-460. 10.1016/j.molcel.2009.04.020.
Itoh T, Iwashita S, Cohen MB, Meyerholz DK, Linn S: Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis. Hum Mol Genet. 2007, 16: 1578-1586. 10.1093/hmg/ddm107.
Kattan Z, Marchal S, Brunner E, Ramacci C, Leroux A, Merlin JL, Domenjoud L, Dauca M, Becuwe P: Damaged DNA binding protein 2 plays a role in breast cancer cell growth. PLoS One. 2008, 3: e2002-10.1371/journal.pone.0002002.
Shivji MK, Grey SJ, Strausfeld UP, Wood RD, Blow JJ: Cip1 inhibits DNA replication but not PCNA-dependent nucleotide excision-repair. Curr Biol. 1994, 4: 1062-1068. 10.1016/S0960-9822(00)00244-X.
Fotedar R, Bendjennat M, Fotedar A: Role of p21WAF1 in the cellular response to UV. Cell Cycle. 2004, 3: 134-137.
Avkin S, Sevilya Z, Toube L, Geacintov N, Chaney SG, Oren M, Livneh Z: p53 and p21 regulate error-prone DNA repair to yield a lower mutation load. Mol Cell. 2006, 22: 407-413. 10.1016/j.molcel.2006.03.022.
Savio M, Coppa T, Cazzalini O, Perucca P, Necchi D, Nardo T, Stivala LA, Prosperi E: Degradation of p21CDKN1A after DNA damage is independent of type of lesion, and is not required for DNA repair. DNA Repair (Amst). 2009, 8: 778-785. 10.1016/j.dnarep.2009.02.005.
Soria G, Speroni J, Podhajcer OL, Prives C, Gottifredi V: p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation. J Cell Sci. 2008, 121: 3271-3282. 10.1242/jcs.027730.
Huang ME, Kolodner RD: A biological network in Saccharomyces cerevisiae prevents the deleterious effects of endogenous oxidative DNA damage. Mol Cell. 2005, 17: 709-720. 10.1016/j.molcel.2005.02.008.
Arner ES, Holmgren A: The thioredoxin system in cancer. Semin Cancer Biol. 2006, 16: 420-426. 10.1016/j.semcancer.2006.10.009.
Liu MT, Chen YR, Chen SC, Hu CY, Lin CS, Chang YT, Wang WB, Chen JY: Epstein-Barr virus latent membrane protein 1 induces micronucleus formation, represses DNA repair and enhances sensitivity to DNA-damaging agents in human epithelial cells. Oncogene. 2004, 23: 2531-2539. 10.1038/sj.onc.1207375.