MDM2 Promotes SUMO-2/3 Modification of P53 to Modulate Transcriptional Activity

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2011 Sep 9

PMID 21900752

Citations 30

Authors

Maren H Stindt

Stephanie Carter

Arnaud M Vigneron

Kevin M Ryan

Karen H Vousden

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor p53 is extensively regulated by post-translational modification, including modification by the small ubiquitin-related modifier SUMO. We show here that MDM2, previously shown to promote ubiquitin, Nedd8 and SUMO-1 modification of p53, can also enhance conjugation of endogenous SUMO-2/3 to p53. Sumoylation activity requires p53-MDM2 binding but does not depend on an intact RING finger. Both ARF and L11 can promote SUMO-2/3 conjugation of p53. However, unlike the previously described SUMO-1 conjugation of p53 by an MDM2-ARF complex, this activity does not depend on the ability of MDM2 to relocalize to the nucleolus. Interestingly, the SUMO consensus is not conserved in mouse p53, which is therefore not modified by SUMO-2/3. Finally, we show that conjugation of SUMO-2/3 to p53 correlates with a reduction of both activation and repression of a subset of p53-target genes.

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References

Azuma Y, Arnaoutov A, Dasso M . SUMO-2/3 regulates topoisomerase II in mitosis. J Cell Biol. 2003; 163(3):477-87. PMC: 2173648. DOI: 10.1083/jcb.200304088. View

Melchior F, Hengst L . SUMO-1 and p53. Cell Cycle. 2002; 1(4):245-9. View

Gostissa M, Hengstermann A, Fogal V, Sandy P, Schwarz S, Scheffner M . Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 1999; 18(22):6462-71. PMC: 1171709. DOI: 10.1093/emboj/18.22.6462. View

Desterro J, Thomson J, Hay R . Ubch9 conjugates SUMO but not ubiquitin. FEBS Lett. 1997; 417(3):297-300. DOI: 10.1016/s0014-5793(97)01305-7. View

Wilkinson K, Henley J . Mechanisms, regulation and consequences of protein SUMOylation. Biochem J. 2010; 428(2):133-45. PMC: 3310159. DOI: 10.1042/BJ20100158. View

Fang S, Jensen J, Ludwig R, Vousden K, Weissman A . Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem. 2000; 275(12):8945-51. DOI: 10.1074/jbc.275.12.8945. View

Carter S, Bischof O, Dejean A, Vousden K . C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol. 2007; 9(4):428-35. DOI: 10.1038/ncb1562. View

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

Ho J, Benchimol S . Transcriptional repression mediated by the p53 tumour suppressor. Cell Death Differ. 2003; 10(4):404-8. DOI: 10.1038/sj.cdd.4401191. View

10.

Vertegaal A . SUMO chains: polymeric signals. Biochem Soc Trans. 2010; 38(Pt 1):46-9. DOI: 10.1042/BST0380046. View

11.

Ulrich H . The fast-growing business of SUMO chains. Mol Cell. 2008; 32(3):301-5. DOI: 10.1016/j.molcel.2008.10.010. View

12.

Poyurovsky M, Priest C, Kentsis A, Borden K, Pan Z, Pavletich N . The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J. 2006; 26(1):90-101. PMC: 1782380. DOI: 10.1038/sj.emboj.7601465. View

13.

Lukashchuk N, Vousden K . Ubiquitination and degradation of mutant p53. Mol Cell Biol. 2007; 27(23):8284-95. PMC: 2169174. DOI: 10.1128/MCB.00050-07. View

14.

Chen L, Chen J . MDM2-ARF complex regulates p53 sumoylation. Oncogene. 2003; 22(34):5348-57. DOI: 10.1038/sj.onc.1206851. View

15.

Li T, Santockyte R, Shen R, Tekle E, Wang G, Yang D . Expression of SUMO-2/3 induced senescence through p53- and pRB-mediated pathways. J Biol Chem. 2006; 281(47):36221-7. DOI: 10.1074/jbc.M608236200. View

16.

Chen J, Lin J, Levine A . Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene. Mol Med. 1995; 1(2):142-52. PMC: 2229942. View

17.

Weger S, Hammer E, Heilbronn R . Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett. 2005; 579(22):5007-12. DOI: 10.1016/j.febslet.2005.07.088. View

18.

Lohrum M, Ashcroft M, Kubbutat M, Vousden K . Identification of a cryptic nucleolar-localization signal in MDM2. Nat Cell Biol. 2000; 2(3):179-81. DOI: 10.1038/35004057. View

19.

Yuan H, Zhou J, Deng M, Liu X, Le Bras M, de The H . Small ubiquitin-related modifier paralogs are indispensable but functionally redundant during early development of zebrafish. Cell Res. 2009; 20(2):185-96. DOI: 10.1038/cr.2009.101. View

20.

Liu G, Xirodimas D . NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways. Oncogene. 2010; 29(15):2252-61. DOI: 10.1038/onc.2009.494. View