The p53 orchestra: Mdm2 and Mdmx set the tone

Trends in Cell Biology

Volumn 20, Issue 5, 2010, Pages 299-309

  Wade, Mark ^a   Wang, Yunyuan V ^a   Wahl, Geoffrey M ^a  

^a SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

NOTCH RECEPTOR; PROTEIN MDM2; PROTEIN MDMX; PROTEIN P53; UBIQUITIN PROTEIN LIGASE E3;

CARBOXY TERMINAL SEQUENCE; DNA DAMAGE; EPITHELIUM; HOMEOSTASIS; MALIGNANT NEOPLASTIC DISEASE; MESENCHYME; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN DNA INTERACTION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; REGULATORY MECHANISM; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; STOICHIOMETRY; UBIQUITINATION;

ANIMALS; HUMANS; MODELS, BIOLOGICAL; NUCLEAR PROTEINS; PHOSPHORYLATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-MDM2; TUMOR SUPPRESSOR PROTEIN P53; UBIQUITINATION;

EID: 77952543499     PISSN: 09628924     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tcb.2010.01.009     Document Type: Review

References (129)

1. Marine J.C., et al. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 2006, 13:927-934.
2. Kruse J.P., Gu W. Modes of p53 regulation. Cell 2009, 137:609-622.
3. Wang Y.V., et al. Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104:12365-12370.
4. Ohtsubo C., et al. Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2. Cancer Sci. 2009, 100:1291-1299.
5. Moll U.M., Petrenko O. The MDM2-p53 interaction. Mol. Cancer Res. 2003, 1:1001-1008.
6. Stommel J.M., et al. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 1999, 18:1660-1672.
7. Marchenko N.D., et al. Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ. 2009, 17:255-267.
8. Kostic M., et al. Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53. J. Mol. Biol. 2006, 363:433-450.
9. Deshaies R.J., Joazeiro C.A.P. RING Domain E3 Ubiquitin Ligases. Annual Review of Biochemistry 2009, 78:399-434.
10. Linares L.K., et al. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl. Acad. Sci. U. S. A. 2003, 100:12009-12014.
11. Brooks C.L., Gu W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 2006, 21:307-315.
12. Stommel J.M., Wahl G.M. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004, 23:1547-1556.
13. Fang S., et al. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 2000, 275:8945-8951.
14. de Graaf P., et al. Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J. Biol. Chem. 2003, 278:38315-38324.
15. Kawai H., et al. DNA damage-induced MDMX degradation is mediated by MDM2. J. Biol. Chem. 2003, 278:45946-45953.
16. Pan Y., Chen J. MDM2 promotes ubiquitination and degradation of MDMX. Mol. Cell Biol. 2003, 23:5113-5121.
17. Tanimura S., et al. MDM2 interacts with MDMX through their RING finger domains. FEBS Lett. 1999, 447:5-9.
18. Hashizume R., et al. The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 2001, 276:14537-14540.
19. Brzovic P.S., et al. Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc. Natl. Acad. Sci. U. S. A. 2003, 100:5646-5651.
20. Linke K., et al. Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ. 2008, 15:841-848.
21. Christensen D.E., et al. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat. Struct. Mol. Biol. 2007, 14:941-948.
22. Ye Y., Rape M. Building ubiquitin chains: E2 enzymes at work. Nat. Rev. Mol. Cell Biol. 2009, 10:755-764.
23. Honda R., et al. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997, 420:25-27.
24. Saville M.K., et al. Regulation of p53 by the Ubiquitin-conjugating Enzymes UbcH5B/C in Vivo. J. Biol. Chem. 2004, 279:42169-42181.
25. van Wijk S.J., et al. A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system. Mol. Syst. Biol. 2009, 5:295.
26. Markson G., et al. Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network. Genome Res. 2009, 19:1905-1911.
27. Uldrijan S., et al. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J. 2007, 26:102-112.
28. Poyurovsky M.V., et al. The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J. 2007, 26:90-101.
29. Cheng Q., et al. ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J. 2009, 28:3857-3867.
30. Wang Y.V., et al. Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations that Prevent Modifications by DNA-Damage-Activated Kinases. Cancer Cell 2009, 16:33-43.
31. Itahana K., et al. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 2007, 12:355-366.
32. Boesten L.S., et al. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death. Cell Death Differ. 2006, 13:2089-2098.
33. Francoz S., et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc. Natl. Acad. Sci. U. S. A. 2006, 103:3232-3237.
34. Grier J.D., et al. Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Mol. Cell Biol. 2006, 26:192-198.
35. Maetens M., et al. Distinct roles of Mdm2 and Mdm4 in red cell production. Blood 2007, 109:2630-2633.
36. Ringshausen I., et al. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 2006, 10:501-514.
37. Valentin-Vega Y.A., et al. Mdm4 loss in the intestinal epithelium leads to compartmentalized cell death but no tissue abnormalities. Differentiation 2009, 77:442-449.
38. Valentin-Vega Y.A., et al. The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival. Cell Death Differ 2008, 15:1772-1781.
39. Xiong S., et al. Loss of Mdm4 results in p53-dependent dilated cardiomyopathy. Circulation 2007, 115:2925-2930.
40. Xiong S., et al. Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc. Natl. Acad. Sci. U. S. A. 2006, 103:3226-3231.
41. Pereg Y., et al. Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:5056-5061.
42. Okamoto K., et al. Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase. FEBS Lett. 2009, 583:2710-2714.
43. Varfolomeev E., et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 2007, 131:669-681.
44. Lee J.T., Gu W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 2010, 17:86-92.
45. Li M., et al. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol. Cell 2004, 13:879-886.
46. Meulmeester E., et al. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol. Cell 2005, 18:565-576.
47. Allende-Vega N., et al. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 2010, 29:432-441.
48. Stevenson L.F., et al. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007, 26:976-986.
49. Marine J.C., et al. MDMX: from bench to bedside. J. Cell Sci. 2007, 120:371-378.
50. Meek D.W., Knippschild U. Posttranslational Modification of MDM2. Molecular Cancer Research 2003, 1:1017-1026.
51. Roos W.P., Kaina B. DNA damage-induced cell death by apoptosis. Trends Mol. Med. 2006, 12:440-450.
52. Mayo L.D., et al. Mdm-2 Phosphorylation by DNA-dependent Protein Kinase Prevents Interaction with p53. Cancer Res. 1997, 57:5013-5016.
53. Zuckerman V., et al. c-Abl Phosphorylates Hdmx and Regulates Its Interaction with p53. Journal of Biological Chemistry 2009, 284:4031-4039.
54. Maya R., et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 2001, 15:1067-1077.
55. Chen L., et al. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J. 2005, 24:3411-3422.
56. LeBron C., et al. Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. EMBO J. 2006, 25:1196-1206.
57. Okamoto K., et al. DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation. Mol. Cell Biol. 2005, 25:9608-9620.
58. Pereg Y., et al. Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage. Mol. Cell. Biol. 2006, 26:6819-6831.
59. Zhang X., et al. Phosphorylation and Degradation of MdmX Is Inhibited by Wip1 Phosphatase in the DNA Damage Response. Cancer Res. 2009, 69:7960-7968.
60. Lu X., et al. The Wip1 phosphatase and Mdm2: cracking the " Wip" on p53 stability. Cell Cycle 2008, 7:164-168.
61. Lu X., et al. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 2005, 19:1162-1174.
62. Mayo L.D., Donner D.B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl. Acad. Sci. U. S. A. 2001, 98:11598-11603.
63. Moumen A., et al. Met acts on Mdm2 via mTOR to signal cell survival during development. Development 2007, 134:1443-1451.
64. Lopez-Pajares V., et al. Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding. J. Biol. Chem. 2008, 283:13707-13713.
65. Winter M., et al. Protein kinase CK1delta phosphorylates key sites in the acidic domain of murine double-minute clone 2 protein (MDM2) that regulate p53 turnover. Biochemistry 2004, 43:16356-16364.
66. Sakaguchi K., et al. Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J. Biol. Chem. 2000, 275:9278-9283.
67. Chen L., et al. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol. Cell Biol. 2005, 25:6509-6520.
68. Kulikov R., et al. Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance. Mol. Cell Biol. 2005, 25:7170-7180.
69. Toledo F., Wahl G.M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat. Rev. Cancer 2006, 6:909-923.
70. Chao C., et al. Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. EMBO J. 2006, 25:2615-2622.
71. MacPherson D., et al. Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23. EMBO J. 2004, 23:3689-3699.
72. Sluss H.K., et al. Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice. Mol. Cell Biol. 2004, 24:976-984.
73. Wu Z., et al. Mutation of Mouse p53 Ser23 and the Response to DNA Damage. Mol. Cell Biol. 2002, 22:2441-2449.
74. Bond G.L., et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 2006, 66:5104-5110.
75. Bond G.L., et al. 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.
76. Wang P., et al. Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells. Oncogene 2008, 27:1590-1598.
77. Terzian T., et al. Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol. Cell Biol. 2007, 27:5479-5485.
78. Murphy D.J., et al. Distinct Thresholds Govern Myc's Biological Output In Vivo. Cancer Cell 2008, 14:447-457.
79. Kawamura T., et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 2009, 460:1140-1144.
80. Krizhanovsky V., Lowe S.W. Stem cells: The promises and perils of p53. Nature 2009, 460:1085-1086.
81. Weber J.D., et al. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999, 1:20-26.
82. Zhang Y., Lu H. Signaling to p53: ribosomal proteins find their way. Cancer Cell 2009, 16:369-377.
83. Wang X., et al. MDM2 and MDMX can interact differently with ARF and members of the p53 family. FEBS Lett 2001, 490:202-208.
84. Sabbatini P., McCormick F. MDMX inhibits the p300/CBP-mediated acetylation of p53. DNA Cell Biol 2002, 21:519-525.
85. Kadakia M., et al. MdmX inhibits Smad transactivation. Oncogene 2002, 21:8776-8785.
86. Jackson M.W., et al. MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. J. Biol. Chem. 2001, 276:25336-25341.
87. Grossman S.R., et al. p300/MDM2 complexes participate in MDM2-mediated p53 degradation. Mol. Cell 1998, 2:405-415.
88. Gilkes D.M., et al. MDMX regulation of p53 response to ribosomal stress. EMBO J. 2006, 25:5614-5625.
89. Ghosh M., et al. MdmX inhibits ARF mediated Mdm2 sumoylation. Cell Cycle 2005, 4:604-608.
90. Ferreon J.C., et al. Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:6591-6596.
91. Marine J.C., Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 2010, 17:93-102.
92. Prives C., White E. Does control of mutant p53 by Mdm2 complicate cancer therapy?. Genes & Development 2008, 22:1259-1264.
93. Colaluca I.N., et al. NUMB controls p53 tumour suppressor activity. Nature 2008, 451:76-80.
94. Beverly L.J., et al. Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression. Cancer Res. 2005, 65:7159-7168.
95. Dotto G.P. Crosstalk of Notch with p53 and p63 in cancer growth control. Nat. Rev. Cancer 2009, 9:587-595.
96. Kopan R., Ilagan M.X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009, 137:216-233.
97. Polyak K., Weinberg R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 2009, 9:265-273.
98. Yang J.-Y., et al. MDM2 Promotes Cell Motility and Invasiveness by Regulating E-Cadherin Degradation. Mol. Cell. Biol. 2006, 26:7269-7282.
99. Khor L.Y., et al. MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02. J. Clin. Oncol. 2009, 27:3177-3184.
100. Jones S.N., et al. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc. Natl. Acad. Sci. U. S. A. 1998, 95:15608-15612.
101. Wang S.-P., et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat. Cell Biol. 2009, 11:694-704.
102. Shangary S., et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:3933-3938.
103. Vassilev L.T., et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303:844-848.
104. Wade M., Wahl G.M. Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?. Mol. Cancer Res. 2009, 7:1-11.
105. Aranda-Anzaldo A., Dent M.A.R. Reassessing the role of p53 in cancer and ageing from an evolutionary perspective. Mechanisms of Ageing and Development 2007, 128:293-302.
106. Kang H.J., et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:9761-9766.
107. Pearson B.J., Sanchez Alvarado A. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages. Development 2010, 137:213-221.
108. Lu W.-J., et al. p53 ancestry: gazing through an evolutionary lens. Nat. Rev. Cancer 2009, 9:758-762.
109. Minsky N., Oren M. The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol. Cell 2004, 16:631-639.
110. Carter S., et al. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat. Cell Biol. 2007, 9:428-435.
111. Li M., et al. Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2. Science 2003, 302:1972-1975.
112. Joseph T.W., et al. Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage. Faseb. J. 2003, 17:1622-1630.
113. Marchenko N.D., et al. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J. 2007, 26:923-934.
114. Mancini F., et al. MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway. EMBO J. 2009, 28:1926-1939.
115. Wade M., et al. BH3 activation blocks Hdmx suppression of apoptosis and co-operates with Nutlin to induce cell death. Cell Cycle 2008, 7:1973-1982.
116. Gostissa M., et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 1999, 18:6462-6471.
117. Rodriguez M.S., et al. SUMO-1 modification activates the transcriptional response of p53. EMBO J 1999, 18:6455-6461.
118. Stehmeier P., Muller S. Regulation of p53 family members by the ubiquitin-like SUMO system. DNA Repair 2009, 8:491-498.
119. Chen L., Chen J. MDM2-ARF complex regulates p53 sumoylation. Oncogene 2003, 22:5348-5357.
120. Xirodimas D.P., et al. P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2. FEBS Lett 2002, 528:207-211.
121. Di Ventura B., et al. Reconstitution of Mdm2-dependent post-translational modifications of p53 in yeast. PLoS ONE 2008, 3:e1507.
122. Mauri F., et al. Modification of Drosophila p53 by SUMO Modulates Its Transactivation and Pro-apoptotic Functions. J. Biol. Chem. 2008, 283:20848-20856.
123. Kwek S.S., Tyner D.J., Shen A.L., Gudkov AV Z. Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 2001, 20:2587-2599.
124. Xirodimas D.P., et al. Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity. Cell 2004, 118:83-97.
125. Sundqvist A., et al. Regulation of nucleolar signalling to p53 through NEDDylation of L11. EMBO Rep 2009, 10:1132-1139.
126. Tang Y., et al. Acetylation is indispensable for p53 activation. Cell 2008, 133:612-626.
127. Wu S.Y., Chiang C.M. Crosstalk between sumoylation and acetylation regulates p53-dependent chromatin transcription and DNA binding. EMBO J 2009, 28:1246-1259.
128. Krummel K.A., et al. The C-terminal lysines fine-tune p53 stress responses in a mouse model, but are not required for stability control or transactivation. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:10188-10193.
129. Feng L., et al. Functional analysis of the roles of posttranslational modifications at the p53C terminus in regulating p53 stability and activity. Mol. Cell Biol. 2005, 25:5389-5395.