Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer

Wang,Lixin; Wang,Lei; Zhang,Shuping; Qu,Guangbo; Zhang,Daoqiang; Li,Shitao; Liu,Sijin

doi:10.3892/or.2012.2121

January 2013 Volume 29 Issue 1

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January 2013 Volume 29 Issue 1

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Article

Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer

Authors:
- Lixin Wang
- Lei Wang
- Shuping Zhang
- Guangbo Qu
- Daoqiang Zhang
- Shitao Li
- Sijin Liu
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Affiliations: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, P.R. China, Division of immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
Pages: 283-287
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Published online on: November 1, 2012

https://doi.org/10.3892/or.2012.2121
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Abstract

p53 is a key tumor suppressor and a master regulator of various signaling pathways, such as those related to apoptosis, cell cycle and DNA repair. In this study, we found a pronounced cytosolic accumulation of the p53 protein in a panel of breast cancer specimens. Several mutations lead to p53 accumulation by disruption of MDM2-mediated p53 degradation. However, gene sequencing revealed no p53 mutation in the majority of our samples. Through search for other possible p53 E3 ligases by mRNA and protein expression analysis, downregulation of TNF receptor-associated factor 7 (TRAF7) expression was found in these breast tumors. We further identified TRAF7 as an E3 ligase for K48-linked ubiquitination of p53 in vitro. These results suggested that the p53 accumulation was due to the defects of TRAF7-mediated ubiquitination. The downregulation of TRAF7 also correlated with poor prognosis in a breast cancer cohort. Collectively, TRAF7-mediated ubiquitination of p53 plays a critical role in breast cancer development, and these insights may aid in the development of novel therapeutic strategies for breast cancer.

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1	Hollstein M, Sidransky D, Vogelstein B and Harris C: p53 mutations in human cancers. Science. 253:49–53. 1991. View Article : Google Scholar : PubMed/NCBI
2	Scudiero I, Zotti T, Ferravante A, et al: Tumor necrosis factor (TNF) receptor-associated factor 7 is required for TNFα-induced Jun NH2-terminal kinase activation and promotes cell death by regulating polyubiquitination and lysosomal degradation of c-FLIP protein. J Biol Chem. 287:6053–6061. 2012.
3	Zotti T, Uva A, Ferravante A, et al: TRAF7 protein promotes Lys-29-linked polyubiquitination of IκB kinase (IKKγ)/NF-κB essential modulator (NEMO) and p65/RelA protein and represses NF-κB activation. J Biol Chem. 286:22924–22933. 2011.PubMed/NCBI
4	Tsikitis M, Acosta-Alvear D, Blais A, et al: Traf7, a MyoD1 transcriptional target, regulates nuclear factor-κB activity during myogenesis. EMBO Rep. 11:969–976. 2010.PubMed/NCBI
5	Patocs A, Zhang L, Xu Y, et al: Breast-cancer stromal cells with TP53 mutations and nodal metastases. N Engl J Med. 357:2543–2551. 2007. View Article : Google Scholar : PubMed/NCBI
6	Kusser WC, Levin DB and Glickman BW: Sensitive two-stage PCR of p53 genomic DNA exons 5–9. PCR Methods Appl. 2:250–252. 1993.
7	Liu S, Goldstein RH, Scepansky EM and Rosenblatt M: Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone. Cancer Res. 69:8742–8751. 2009. View Article : Google Scholar : PubMed/NCBI
8	Liu S, Li S and Du Y: Polychlorinated biphenyls (PCBs) enhance metastatic properties of breast cancer cells by activating Rho-associated kinase (ROCK). PLoS One. 5:e112722010. View Article : Google Scholar : PubMed/NCBI
9	Jamshidi M, Bartkova J, Greco D, et al: NQO1 expression correlates inversely with NFκB activation in human breast cancer. Breast Cancer Res Treat. 132:955–968. 2012.
10	Silvestrini R, Daidone MG, Benini E, et al: Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers. Clin Cancer Res. 2:2007–2013. 1996.PubMed/NCBI
11	Sjögren S, Inganäs M, Norberg T, et al: The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst. 88:173–182. 1996.
12	Moll UM, Riou G and Levine AJ: Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci USA. 89:7262–7266. 1992. View Article : Google Scholar : PubMed/NCBI
13	Häcker H, Tseng PH and Karin M: Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol. 11:457–468. 2011.PubMed/NCBI
14	Zotti T, Vito P and Stilo R: The seventh ring: exploring TRAF7 functions. J Cell Physiol. 227:1280–1284. 2012. View Article : Google Scholar : PubMed/NCBI
15	Lacroix M, Toillon RA and Leclercq G: p53 and breast cancer, an update. Endocr Relat Cancer. 13:293–325. 2006. View Article : Google Scholar : PubMed/NCBI
16	Lee JT and Gu W: The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 17:86–92. 2009.
17	O’Brate A and Giannakakou P: The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Updat. 6:313–322. 2003.PubMed/NCBI
18	Liang SH and Clarke MF: Regulation of p53 localization. Eur J Biochem. 268:2779–2783. 2001. View Article : Google Scholar : PubMed/NCBI
19	Mullany LK, Liu Z, King ER, Wong KK and Richards JS: Wild-type tumor repressor protein 53 (Trp53) promotes ovarian cancer cell survival. Endocrinology. 153:1638–1648. 2012. View Article : Google Scholar : PubMed/NCBI
20	Houben R, Hesbacher S, Schmid CP, et al: High-level expression of wild-type p53 in melanoma cells is frequently associated with inactivity in p53 reporter gene assays. PLoS One. 6:e220962011. View Article : Google Scholar : PubMed/NCBI
21	Wang YC, Lin RK, Tan YH, Chen JT, Chen CY and Wang YC: Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations: an alternative pathway to non-small cell lung cancer. J Clin Oncol. 23:154–164. 2005. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer

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