title: SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization.
abstract: Steroid receptor coactivator 3 (SRC-3) is an oncogenic nuclear receptor coactivator that plays a significant role in drug resistance. Using a lentiviral cDNA library rescue screening approach, we identified a SRC-3 downstream gene-TRAF4 (tumor necrosis factor [TNF] receptor associated-factor 4)-that functions in cell resistance to cytotoxic stress. TRAF4 expression is positively correlated with SRC-3 expression in human breast cancers. Similar to that observed for SRC-3 overexpression, breast cancer cells overexpressing TRAF4 are more resistant to stress-induced death. Here, we further dissected the underlying molecular mechanism for SRC-3 and TRAF4-mediated resistance to cytotoxic agents. We observed that SRC-3 expression is inversely correlated with the expression of p53-regulated proapoptotic genes in breast cancers and further found that SRC-3 and TRAF4 overexpression diminished cytotoxic stress-induced up-regulation of the tumor suppressor p53 protein. To determine the mechanism, we showed that the TRAF domain of TRAF4 bound to the N-terminal TRAF-like region of the deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also named USP7) and blocked the access of p53 to the same region of HAUSP. This TRAF4-mediated inhibition of HAUSP then led to the loss of p53 deubiquitination and its stabilization in response to cellular stress. Consistent with this cellular function, we also found that TRAF4 overexpression in breast cancer patients was associated significantly with poor prognosis. Because of SRC-3's ability to abrogate p53 function, our results suggest that SRC-3 overexpression may be especially important in tumors in which p53 is not mutated.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Ping
authors: P
authors: Yi
authors: Weiya
authors: W
authors: Xia
authors: Ray-Chang
authors: RC
authors: Wu
authors: David M
authors: DM
authors: Lonard
authors: Mien-Chie
authors: MC
authors: Hung
authors: Bert W
authors: BW
authors: O'Malley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D013312:Stress, Physiological / Q000502:physiology*; D053449:TNF Receptor-Associated Factor 4 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D053449:TNF Receptor-Associated Factor 4; D016159:Tumor Suppressor Protein p53; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D010450:Endopeptidases; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse
references: J Biol Chem. 1995 Oct 27;270(43):25715-21
references: 7592751
references: Science. 2009 Aug 28;325(5944):1134-8
references: 19713527
references: PLoS One. 2011 Apr 27;6(4):e19249
references: 21556366
references: Acta Pharmacol Sin. 2006 Apr;27(4):387-94
references: 16539836
references: Cell Res. 2012 Jun;22(6):1003-21
references: 22430150
references: J Natl Cancer Inst. 2003 Mar 5;95(5):353-61
references: 12618500
references: Clin Cancer Res. 2009 Feb 15;15(4):1417-27
references: 19193619
references: Cancer. 1999 Dec 1;86(11):2259-65
references: 10590366
references: Nat Struct Mol Biol. 2006 Mar;13(3):285-91
references: 16474402
references: Gynecol Oncol. 1999 Aug;74(2):181-7
references: 10419729
references: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5585-90
references: 11943846
references: Science. 1997 Aug 15;277(5328):965-8
references: 9252329
references: Oncogene. 2001 Oct 1;20(44):6482-91
references: 11607847
references: J Biol Chem. 2011 Jul 1;286(26):22924-33
references: 21518757
references: Nature. 2004 Apr 1;428(6982):1 p  following 486
references: 15058298
references: PLoS One. 2008;3(10):e3518
references: 18953416
references: Nat Cell Biol. 2002 Nov;4(11):842-9
references: 12402042
references: Clin Cancer Res. 2004 Jun 1;10(11):3815-24
references: 15173090
references: Prostate. 2009 Nov 1;69(15):1668-82
references: 19670229
references: Clin Exp Metastasis. 2004;21(2):91-106
references: 15168727
references: J Biol Chem. 2001 Jun 29;276(26):24242-52
references: 11279055
references: Adv Exp Med Biol. 2007;597:60-71
references: 17633017
references: J Pathol. 2005 Jan;205(2):275-92
references: 15641020
references: Adv Exp Med Biol. 2008;615:81-104
references: 18437892
references: Immunology. 2008 Aug;124(4):562-74
references: 18284467
references: Cancer Res. 2004 Mar 1;64(5):1875-85
references: 14996752
references: J Biol Chem. 1998 Jul 3;273(27):16651-4
references: 9642216
references: Clin Cancer Res. 2007 Mar 1;13(5):1405-11
references: 17332282
references: Toxicology. 2009 Aug 3;262(2):98-105
references: 19433130
references: Nat Rev Cancer. 2009 Sep;9(9):615-30
references: 19701241
references: Cancer Res. 2010 Aug 15;70(16):6477-85
references: 20663904
references: Am J Pathol. 1998 Jun;152(6):1549-61
references: 9626059
references: Int J Hematol. 2009 Jun;89(5):628-35
references: 19365708
references: Cancer Cell. 2004 Sep;6(3):263-74
references: 15380517
references: Hum Mutat. 2003 Mar;21(3):301-6
references: 12619116
references: Cancer Res. 2000 Nov 15;60(22):6266-71
references: 11103781
references: Mol Cell. 2004 Mar 26;13(6):879-86
references: 15053880
references: Breast Cancer Res Treat. 2008 May;109(2):255-62
references: 17636398
references: Cancer Res. 2008 Jul 1;68(13):5460-8
references: 18593949
references: PLoS Biol. 2006 Feb;4(2):e27
references: 16402859
references: Cancer Sci. 2009 Sep;100(9):1591-6
references: 19552757
references: Nat Cell Biol. 2011 Jan;13(1):102-8
references: 21170034
references: Oncogene. 2007 Jan 4;26(1):142-7
references: 16799635
references: Mol Cell. 2005 May 27;18(5):565-76
references: 15916963
references: Eur J Biochem. 2002 Oct;269(19):4819-29
references: 12354113
references: Eur J Surg Oncol. 2010 Mar;36(3):224-9
references: 19716257
references: Cancer. 2003 Jul 1;98(1):18-23
references: 12833450
references: Nature. 2002 Apr 11;416(6881):648-53
references: 11923872
references: Cell. 1994 Aug 26;78(4):681-92
references: 8069916
references: J Biol Chem. 1998 Apr 17;273(16):9357-60
references: 9545256
references: Nature. 2012 Apr 18;486(7403):346-52
references: 22522925
references: Mol Cell. 2005 Apr 1;18(1):25-36
references: 15808506