Scott Bang and Heeruk C. Bhatt contributed equally.
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References
Barak Y, Juven T, Haffner R, Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993;12:461–8.
Biderman L, Manley JL, Prives C. Mdm2 and MdmX as regulators of gene expression. Genes Cancer. 2012;3:264–73. https://doi.org/10.1177/1947601912455331.
Blattner C, Hay T, Meek DW, Lane DP. Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol. 2002;22:6170–82. https://doi.org/10.1128/MCB.22.17.6170-6182.2002.
Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602. https://doi.org/10.1016/j.cell.2004.11.022.
Boyd SD, Tsai KY, Jacks T. An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat Cell Biol. 2000a;2:563–8. https://doi.org/10.1038/35023500.
Burgess A, Chia KM, Haupt S, Thomas D, Haupt Y, Lim E. Clinical overview of MDM2/X-targeted therapies. Front Oncol. 2016;6:7. https://doi.org/10.3389/fonc.2016.00007.
Cahilly-Snyder L, Yang-Feng T, Francke U, George DL. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3 T3 cell line. Somat Cell Mol Genet. 1987;13:235–44. https://doi.org/10.1007/BF01535205.
Chen J, Marechal VI, Levine AJ. Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol. 1993;13:4107–14. https://doi.org/10.1128/MCB.13.7.4107.
Cheng Q, Chen L, Li Z, Lane WS, Chen J. ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J. 2009;28:3857–67. https://doi.org/10.1038/emboj.2009.294.
Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J. Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage. Mol Cell Biol. 2011;31:4951–63. https://doi.org/10.1128/MCB.05553-11.
Cummins JM, Rago C, Kohli M, Kinzler KW, Lengauer C, Vogelstein B. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature. 2004;428:1. https://doi.org/10.1038/nature02501.
Dei Tos AP, Doglioni C, Piccinin S, Sciot R, Furlanetto A, Boiocchi M, Dal Cin P, Maestro R, Fletcher CD, Tallini G. Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. J Pathol. 2000;190:531–6. https://doi.org/10.1002/(SICI)1096-9896(200004)190:5<531::AID-PATH579>3.0.CO;2-W.
Fakharzadeh SS, Trusko SP, George DL. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 1991;10:1565–9.
Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, Hess D, Hemmings BA. Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem. 2004;279:35510–7. https://doi.org/10.1074/jbc.M404936200.
Ganguli G, Wasylyk B. p53-Independent functions of MDM2. Mol Cancer Res 2003;1:1027–1035.
Gannon HS, Woda BA, Jones SN. ATM Phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice. Cancer Cell. 2012;21:668–79. https://doi.org/10.1016/j.ccr.2012.04.011.
Geyer RK, Zhong KY, Maki CG. The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol. 2000;2:569–73. https://doi.org/10.1038/35023507.
Goldberg Z, Sionov RV, Berger M, Zwang Y, Perets R, Van Etten RA, Oren M, Taya Y, Haupt Y. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J. 2002;21:3715–27. https://doi.org/10.1093/emboj/cdf384.
Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9. https://doi.org/10.1038/387296a0.
He Y, Tollini L, Kim TH, Itahana Y, Zhang Y. The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2. Cell Cycle. 2014;13:2101–9. https://doi.org/10.4161/cc.29106.
Herman AG, Hayano M, Poyurovsky MV, Shimada K, Skouta R, Prives C, Stockwell BR. Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay. Cancer Discov. 2011;1:312–25. https://doi.org/10.1158/2159-8290.CD-11-0104.
Honda R, Yasuda H. Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 1999;18:22–7. https://doi.org/10.1093/emboj/18.1.22.
Honda R, Yasuda H. Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase. Oncogene. 2000;19:1473–6. https://doi.org/10.1038/sj.onc.1203464.
Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25–7. https://doi.org/10.1016/S0014-5793(97)01480-4.
Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG, Zuo Y, Kawai H, Shadfan M, Ganapathy S, Yuan ZM. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci USA. 2011;108:12001–6. https://doi.org/10.1073/pnas.1102309108.
Inuzuka H, Tseng A, Gao D, Zhai B, Zhang Q, Shaik S, Wan L, Ang XL, Mock C, Yin H, Stommel JM, Gygi S, Lahav G, Asara J, Xiao Z-XJ, Kaelin WG, Harper JW, Wei W. Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCFbeta-TRCP ubiquitin ligase. Cancer Cell. 2010;18:147–59. https://doi.org/10.1016/j.ccr.2010.06.015.
Itahana K, Mao H, Jin A, Itahana Y, Clegg HV, Lindström MS, Bhat KP, Godfrey VL, Evan GI, Zhang Y. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell. 2007;12:355–66. https://doi.org/10.1016/j.ccr.2007.09.007.
Jones SN, Roe AE, Donehower LA, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995;378:206–8. https://doi.org/10.1038/378206a0.
Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA. 1998;95:15608–12. https://doi.org/10.1073/pnas.95.26.15608.
Kawai H, Wiederschain D, Yuan ZM. Critical contribution of the MDM2 acidic domain to p53 ubiquitination. Mol Cell Biol. 2003;23:4939–47. https://doi.org/10.1128/MCB.23.14.4939-4947.2003.
Korkolopoulou P, Christodoulou P, Kouzelis K, Hadjiyannakis M, Priftis A, Stamoulis G, Seretis A, Thomas-Tsagli E. MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br J Cancer. 1997;75:1269–78.
Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 2015;16:393–405. https://doi.org/10.1038/nrm4007.
Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387:299–303. https://doi.org/10.1038/387299a0.
Kurokawa M, Kim J, Geradts J, Matsuura K, Liu L, Ran X, Xia W, Ribar TJ, Henao R, Dewhirst MW, Kim WJ. A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci Signal. 2013;6:ra32. https://doi.org/10.1126/scisignal.2003741.
Li J, Kurokawa M. Regulation of MDM2 stability after DNA damage. J Cell Physiol. 2015;230:2318–27. https://doi.org/10.1002/jcp.24994.
Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science. 2003;302:1972–5. https://doi.org/10.1126/science.1091362.
Linares LK, Kiernan R, Triboulet R, Chable-Bessia C, Latreille D, Cuvier O, Lacroix M, Le Cam L, Coux O, Benkirane M. Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2. Nat Cell Biol. 2007;9:331–8. https://doi.org/10.1038/ncb1545.
Liu Y, He Y, Jin A, Tikunov AP, Zhou L, Tollini LA, Leslie P, Kim TH, Li LO, Coleman RA, Gu Z. Ribosomal protein–Mdm2–p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation. Proc Natl Acad Sci USA. 2014;111:E2414–22. https://doi.org/10.1073/pnas.1315605111.
Lu X, Ma O, Nguyen TA, Jones SN, Oren M, Donehower LA. The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory Loop. Cancer Cell. 2007;12:342–54. https://doi.org/10.1016/j.ccr.2007.08.033.
Malonia SK, Dutta P, Santra MK, Green MR. F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress. Proc Natl Acad Sci USA. 2015;112:8632–7. https://doi.org/10.1073/pnas.1510929112.
Mayo LD, Turchi JJ, Berberich SJ. Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res. 1997;57:5013–6.
Moll UM, Petrenko O. The MDM2-p53 interaction. Mol Cancer Res. 2003;1:1001–8.
Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992;69:1237–45. https://doi.org/10.1016/0092-8674(92)90644-R.
Montes de Oca Luna R, Wagner DS, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995;378:203–6. https://doi.org/10.1038/378203a0.
Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992;358:80–3. https://doi.org/10.1038/358080a0.
Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993;362:857–60. https://doi.org/10.1038/362857a0.
Pant V, Xiong S, Iwakuma T, Quintás-Cardama A, Lozano G. Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability. Proc Natl Acad Sci USA. 2011;108:11995–2000. https://doi.org/10.1073/pnas.1102241108.
Perry ME, Piette J, Zawadzki JA, Harvey D, Levine AJ. The mdm-2 gene is induced in response to UV light in a p53-dependent manner. Proc Natl Acad Sci USA. 1993;90:11623–7. https://doi.org/10.1073/pnas.90.24.11623.
Phillips CL, Gerbing R, Alonzo T, Perentesis JP, Harley IT, Meshinchi S, Bhatla D, Radloff G, Davies SM. MDM2 polymorphism increases susceptibility to childhood acute myeloid leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2010;55:248–53. https://doi.org/10.1002/pbc.22519.
Post SM, Pant V, Abbas H, Quintás-Cardama A. Prognostic impact of the MDM2SNP309 allele in leukemia and lymphoma. Oncotarget. 2010;1:168–74. https://doi.org/10.18632/oncotarget.100712.
Riley MF, Lozano G. The many faces of MDM2 binding partners. Genes Cancer. 2012;3:226–39. https://doi.org/10.1177/1947601912455322.
Roth J, Dobbelstein M, Freedman DA, Shenk T, Levine AJ. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J. 1998;17:554–64. https://doi.org/10.1093/emboj/17.2.554.
Roxburgh P, Hock AK, Dickens MP, Mezna M, Fischer PM, Vousden KH. Small molecules that bind the Mdm2 RING stabilize and activate p53. Carcinogenesis. 2012;33:791–8. https://doi.org/10.1093/carcin/bgs092.
Sherr CJ. Divorcing ARF and p53: an unsettled case. Nat Rev Cancer. 2006;6:663–73. https://doi.org/10.1038/nrc1954.
Shieh SY, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997;91:325–34. https://doi.org/10.1016/S0092-8674(00)80416-X.
Shinozaki T, Nota A, Taya Y, Okamoto K. Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export. Oncogene. 2003;22:8870–80. https://doi.org/10.1038/sj.onc.1207176.
Singh RK, Iyappan S, Scheffner M. Hetero-oligomerization with MdmX rescues the ubiquitin/Nedd8 ligase activity of RING finger mutants of Mdm2. J Biol Chem. 2007;282:10901–7. https://doi.org/10.1074/jbc.M610879200.
Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP, Saville MK, Jochemsen AG. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep. 2001;2:1029–34. https://doi.org/10.1093/embo-reports/kve227.
Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007;26:976–86. https://doi.org/10.1038/sj.emboj.7601567.
Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004;23:1547–56. https://doi.org/10.1038/sj.emboj.7600145.
Tao W, Levine AJ. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc Natl Acad Sci USA. 1999a;96:3077–80. https://doi.org/10.1073/pnas.96.6.3077.
Tao W, Levine AJ. p19ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci USA. 1999b;96:6937–41. https://doi.org/10.1073/pnas.96.12.6937.
Tollini LA, Jin A, Park J, Zhang Y. Regulation of p53 by Mdm2 E3 ligase function is dispensable in embryogenesis and development, but essential in response to DNA damage. Cancer Cell. 2014;26:235–47. https://doi.org/10.1016/j.ccr.2014.06.006.
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8. https://doi.org/10.1126/science.1092472.
Watanabe T, Hotta T, Ichikawa A, Kinoshita T, Nagai H, Uchida T, Murate T, Saito H. The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin. Blood. 1994;84:3158–65.
Watanabe T, Ichikawa A, Saito H, Hotta T. Overexpression of the MDM2 oncogene in leukemia and lymphoma. Leuk Lymphoma. 1996;21:391–7. https://doi.org/10.3109/10428199609093436.
Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol. 1999;1:20–6. https://doi.org/10.1038/8991.
Yu GW, Rudiger S, Veprintsev D, Freund S, Fernandez-Fernandez MR, Fersht AR. The central region of HDM2 provides a second binding site for p53. Proc Natl Acad Sci USA. 2006;103:1227–32. https://doi.org/10.1073/pnas.0510343103.
Zhang Y, Lu H. Signaling to p53: ribosomal proteins find their way. Cancer Cell. 2009;16:369–77. https://doi.org/10.1016/j.ccr.2009.09.024.
Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001;3:973–82. https://doi.org/10.1038/ncb1101-973.
Zhuo W, Zhang L, Ling J, Zhu B, Chen Z. MDM2 SNP309 variation contributes to leukemia risk: meta-analyses based on 7259 subjects. Leuk Lymphoma. 2012;53:2245–52. https://doi.org/10.3109/10428194.2012.691485.
Zou Q, Jin J, Hu H, Li HS, Romano S, Xiao Y, Nakaya M, Zhou X, Cheng X, Yang P, Lozano G. USP15 stabilizes MDM2 to mediate cancer cell survival and inhibit antitumor T cell responses. Nat Immunol. 2014;15:562–70. https://doi.org/10.1038/ni.2885.
Acknowledgments
The authors acknowledge support from an NCI Career Development Award R00 CA140948 (to M.K.), American Cancer Society Institutional Research Grant IRG-82-003-30 (to M.K.), a Norris Cotton Cancer Center Prouty Grant (to M.K.), a Norris Cotton Cancer Center Leukemia/Lymphoma Fund (to M.K.), and Waterhouse Research Award (to Y.Y.C.).
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Bang, S., Bhatt, H.C., Chen, Y.Y., Kurokawa, M. (2018). MDM2 (Murine Double Minute 2). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101574
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