TRIM45 functions as a tumor suppressor in the brain via its E3 ligase activity by stabilizing p53 through K63-linked ubiquitination

Cell Death and Disease - Tập 8 Số 5 - Trang e2831-e2831
Jindong Zhang1, Chuanxia Zhang2, Jun Cui3, Jiayu Ou1, Jing Han1, Yunfei Qin2, Feng Zhi4, Rong‐Fu Wang5
1Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, People's Republic of China,
2Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China,
3Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
4Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou 213000, People's Republic of China,
5Center for Inflammation and Epigenetics, Houston Methodist Research Institute, 6670 Betner Avenue, Houston, 77096, TX, USA

Tóm tắt

Abstract

Tripartite motif-containing protein 45 (TRIM45) belongs to a large family of RING-finger-containing E3 ligases, which are highly expressed in the brain. However, little is known regarding the role of TRIM45 in cancer biology, especially in human glioma. Here, we report that TRIM45 expression is significantly reduced in glioma tissue samples. Overexpression of TRIM45 suppresses proliferation and tumorigenicity in glioblastoma cells in vitro and in vivo. In addition, CRISPR/Cas9-mediated knockout of TRIM45 promotes proliferation and inhibits apoptosis in glioblastoma cells. Further mechanistic analyses show that TRIM45 interacts with and stabilizes p53. TRIM45 conjugates K63-linked polyubiquitin chain to the C-terminal six lysine residues of p53, thereby inhibiting the availability of these residues to the K48-linked polyubiquitination that targets p53 for degradation. These findings suggest that TRIM45 is a novel tumor suppressor that stabilizes and activates p53 in glioma.

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Tài liệu tham khảo

Gladson CL, Prayson RA, Liu WM . The pathobiology of glioma tumors. Annu Rev Pathol 2010; 5: 33–50.

Huse JT, Holland EC . Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010; 10: 319–331.

Dolecek TA, Propp JM, Stroup NE, Kruchko C . CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro-oncology 2012; 14 (Suppl 5): v1–49.

Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ . Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 2010; 60: 166–193.

Wen PY, Kesari S . Malignant gliomas in adults. N Engl J Med 2008; 359: 492–507.

Bieging KT, Mello SS, Attardi LD . Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 2014; 14: 359–370.

Bode AM, Dong Z . Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004; 4: 793–805.

Dai C, Gu W . P53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med 2010; 16: 528–536.

Ashcroft M, Vousden KH . Regulation of p53 stability. Oncogene 1999; 18: 7637–7643.

Hershko A, Ciechanover A . The ubiquitin system. Annu Rev Biochem 1998; 67: 425–479.

Husnjak K, Dikic I . Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 2012; 81: 291–322.

Lee JT, Gu W . The multiple levels of regulation by p53 ubiquitination. Cell Death Differ 2010; 17: 86–92.

Haupt Y, Maya R, Kazaz A, Oren M . Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–299.

Kubbutat MH, Jones SN, Vousden KH . Regulation of p53 stability by Mdm2. Nature 1997; 387: 299–303.

Saurin AJ, Borden KL, Boddy MN, Freemont PS . Does this have a familiar RING? Trends Biochem Sci 1996; 21: 208–214.

Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L et al. The tripartite motif family identifies cell compartments. EMBO J 2001; 20: 2140–2151.

Ozato K, Shin DM, Chang TH, Morse HC III . TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol 2008; 8: 849–860.

Wang Y, Li Y, Qi X, Yuan W, Ai J, Zhu C et al. TRIM45, a novel human RBCC/TRIM protein, inhibits transcriptional activities of ElK-1 and AP-1. Biochem Biophys Res Commun 2004; 323: 9–16.

Sato T, Takahashi H, Hatakeyama S, Iguchi A, Ariga T . The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKC-mediated signaling pathway. Oncogene 2015; 34: 1280–1291.

Shibata M, Sato T, Nukiwa R, Ariga T, Hatakeyama S . TRIM45 negatively regulates NF-kappaB-mediated transcription and suppresses cell proliferation. Biochem Biophys Res Commun 2012; 423: 104–109.

Cancer Genome Atlas Research N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–1068.

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.

Hock A, Vousden KH . Regulation of the p53 pathway by ubiquitin and related proteins. Int J Biochem Cell Biol 2010; 42: 1618–1621.

Wade M, Li YC, Wahl GM . MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96.

Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003; 112: 779–791.

Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 2004; 429: 86–92.

Chen D, Kon N, Li M, Zhang W, Qin J, Gu W . ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 2005; 121: 1071–1083.

Laine A, Ronai Z . Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 2007; 26: 1477–1483.

Laine A, Topisirovic I, Zhai D, Reed JC, Borden KL, Ronai Z . Regulation of p53 localization and activity by Ubc13. Mol Cell Biol 2006; 26: 8901–8913.

Kubbutat MH, Ludwig RL, Ashcroft M, Vousden KH . Regulation of Mdm2-directed degradation by the C terminus of p53. Mol Cell Biol 1998; 18: 5690–5698.

Rodriguez MS, Desterro JM, Lain S, Lane DP, Hay RT . Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol Cell Biol 2000; 20: 8458–8467.

Ito A, Kawaguchi Y, Lai CH, Kovacs JJ, Higashimoto Y, Appella E et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J 2002; 21: 6236–6245.

Li M, Luo J, Brooks CL, Gu W . Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 2002; 277: 50607–50611.

Qin Y, Zhou MT, Hu MM, Hu YH, Zhang J, Guo L et al. RNF26 temporally regulates virus-triggered type I interferon induction by two distinct mechanisms. PLoS Pathog 2014; 10: e1004358.

Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T et al. P53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 1994; 78: 703–711.

Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 2014; 343: 84–87.

Zhang J, Zhang P, Wei Y, Piao HL, Wang W, Maddika S et al. Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol 2013; 15: 1486–1494.

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Cell Death and Disease

Tập 8 Số 5

e2831-e2831

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