The MDM2-p53 pathway revisited

Journal of Biomedical Research

Volumn 27, Issue 4, 2013, Pages 254-271

  Nag, Subhasree ^a   Qin, Jiangjiang ^a   Srivenugopal, Kalkunte S ^a   Wang, Minghai ^a   Zhang, Ruiwen ^a  

^a TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

Author keywords

Cancer therapy; MDM2 p53 interaction; Oncogene; Tumor suppressor

Indexed keywords

EID: 84890416405     PISSN: 16748301     EISSN: None     Source Type: Journal    
DOI: 10.7555/JBR.27.20130030     Document Type: Review

References (163)

1. Croce CM. Oncogenes and cancer. N Engl J Med 2008; 358: 502-11.
2. Zhang Z, Li M, Rayburn ER, Hill DL, Zhang R, Wang H. Oncogenes as novel targets for cancer therapy (part II): Intermediate signaling molecules. Am J Pharmacogenomics 2005; 5: 247-57.
3. Zhang Z, Li M, Rayburn ER, Hill DL, Zhang R, Wang H. Oncogenes as novel targets for cancer therapy (part III): transcription factors. Am J Pharmacogenomics 2005; 5: 327-38.
4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-74.
5. Perera S, Bapat B. Genetic Instability in Cancer. Atlas Genet CytogenetOncolHaematol January 2007. URL: http://AtlasGeneticsOncology.org/Deep/GenetInstabilityCancerID20056.html.
6. Weinstein IB, Joe A. Oncogene addiction. Cancer Res 2008; 68: 3077-80.
7. Letai AG. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Rev Cancer 2008; 8: 121-32.
8. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer 2009; 9: 749-58.
9. Moll, UM, Petrenko O. The MDM2-p53 Interaction. Mol Cancer Res 2003; 1: 1001-08.
10. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998; 26: 3453-9.
11. Zhang, Wang H. MDM2 oncogene as a novel target for human cancer therapy. Curr Pharm Des 2000; 6: 393-416.
12. Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of p53. Cell 2009; 13: 413-31.
13. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 2009; 49: 223-41.
14. Menendez D, Inga A, Resnick MA. The expanding universe of p53 targets. Nat Rev Cancer 2009; 9: 724-37.
15. Ginsberg D, Mechta F, Yaniv M, Oren M. Wild-type p53 can down-modulate the activity of various promoters. Proc Natl Acad Sci U S A 1991; 88: 9979-83.
16. Zhang L, Yu D, Hu M, Xiong S, Lang A, Ellis LM, Pollock RE. Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 2000; 60, 3655-61.
17. Hünten S, Siemens H, Kaller M, Hermeking H. The p53/microRNA Network in Cancer: Experimental and Bioinformatics Approaches. Adv Exp Med Biol 2013; 774: 77-101.
18. Wang L, He G, Zhang P, Wang X, Jiang M, Yu L. Interplay between MDM2, MDMX, Pirh2 and COP1: the negative regulators of p53. Mol Biol Rep 2011; 38: 229-36.
19. Wang Z, Yang B, Dong L, Peng B, He X, Liu W. A novel oncoprotein Pirh2: rising from the shadow of MDM2. Cancer Sci 2011; 102: 909-17.
20. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992; 69: 1237-45.
21. Cahilly-Snyder L, Yang-Feng T, Francke U, George DL. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat Cell Mol Genet 1987; 13: 235-44.
22. 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.
23. 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.
24. Olson DC, Marechal V, Momand J, Chen J, Romocki C, Levine AJ. Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene 1993; 8: 2353-60.
25. Evans SC, Viswanathan M, Grier JD, Narayana M, El-Naggar AK, Lozano G. An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 2001; 20: 4041-9.
26. Perry ME, Mendrysa SM, Saucedo LJ, Tannous P, Holubar M. p76(MDM2) inhibits the ability of p90(MDM2) to destabilize p53. J Biol Chem 2000; 275: 5733-8.
27. Rayburn ER, Ezell SJ, Zhang R. Recent advances in validating MDM2 as a cancer target. Anticancer Agents Med Chem; 2009; 9: 882-903.
28. Grochola LF, Zeron-Medina J, Mériaux S, Bond GL. Single nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb Perspect Biol 2010; 2: a001032. doi: 10.1101/cshperspect.a001032.
29. Schmidt MK, Reincke S, Broeks A, Braaf LM, Hogervorst FB, Tollenaar RA, et al. Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. Cancer Res 2007; 67: 9584-90.
30. Bond GL, Hirshfield KM, KirchhoffT, Alexe G, Bond EE, Robins H, et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 2006; 66: 5104-10.
31. Wan Y, Wu W, Yin Z, Guan P, Zhou B. MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis. BMC cancer. 2011; 11: 208.
32. Wilkening S, Bermejo JL, Hemminki K. MDM2 SNP309 and cancer risk: a combined analysis. Carcinogenesis 2007; 28: 2262-7.
33. Watanabe T, Ichikawa A, Saito H, Hotta T. Overexpression of the MDM2 oncogene in leukemia and lymphoma. Leuk Lymphoma 1996; 21: 391-7.
34. Cordon-Cardo C, Latres E, Drobnjak M, Oliva MR, Pollack D, WoodruffJM, et al. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 1994; 54: 794-9.
35. Rayburn E, Zhang R, He J, Wang H. MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 2005; 5: 27-41.
36. Barak Y, Gottlieb E, Juven-Gershon T, Oren M. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with non-identical translation potential. Genes Dev 1994; 8: 1739-49.
37. Thomasova D, Mulay SR, Bruns H, Anders HJ. p53-independent roles of MDM2 in NF-κB signaling: implications for cancer therapy, wound healing, and autoimmune diseases. Neoplasia 2012; 14: 1097-101.
38. Truong AH, Cervi D, Lee J, Ben-David Y. Direct transcriptional regulation of MDM2 by Fli-1. Oncogene 2005; 24: 962-9.
39. Zhang X, Zhang Z, Cheng J, Li M, Wang W, Xu W, et al. Transcription factor NFAT1 activates the mdm2 oncogene independent of p53. J Biol Chem 2012; 287: 30468-76.
40. Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 2000; 103: 321-30.
41. Zhang J, Sun Q, Zhang Z, Ge S, Han ZG, Chen WT. Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop. Oncogene 2013; 32: 61-9.
42. Dar AA, Majid S, Rittsteuer C, de Semir D, Bezrookove V, Tong S, et al. The Role of miR-18b in MDM2-p53 Pathway Signaling and Melanoma Progression. J Natl Cancer Inst 2013; 105: 433-42.
43. de Toledo SM, Azzam EI, Dahlberg WK, Gooding TB, Little JB. ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation. Oncogene 2000; 19: 6185-93.
44. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 2005; 4: 1166-70.
45. Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 2001; 15: 1067-77.
46. Mayo LD, Donner DB. 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: 11598-603.
47. Gama V, Gomez JA, Mayo LD, Jackson MW, Danielpour D, Song K, et al. Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization. Cell Death Differ 2009; 16: 758-69.
48. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 2002; 277: 21843-50.
49. 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.
50. Asahara H, Li Y, Fuss J, Haines DS, Vlatkovic N, Boyd MT, et al. Stimulation of human DNA polymerase epsilon by MDM2. Nucleic Acids Res 2003; 31: 2451-9.
51. Vlatkovic N, Guerrera S, Li Y, Linn S, Haines DS, Boyd MT. MDM2 interacts with the C-terminus of the catalytic subunit of DNA polymerase epsilon. Nucleic Acids Res 2000; 28: 3581-6.
52. Maguire M, Nield PC, Devling T, Jenkins RE, Park BK, Polański R, et al. MDM2 regulates dihydrofolatereductase activity through monoubiquitination. Cancer Res 2008; 68: 3232-42.
53. Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, et al. Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 1999; 18: 1935-44.
54. Alt JR, Bouska A, Fernandez MR, Cerny RL, Xiao H, Eischen CM. Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair. J Biol Chem 2005; 280: 18771-81.
55. Bouska A, Lushnikova T, Plaza S, Eischen CM. Mdm2 promotes genetic instability and transformation independent of p53. Mol Cell Biol 2008; 28: 4862-74.
56. Hsieh JK, Chan FS, O'Connor DJ, Mittnacht S, Zhong S, Lu X. RB regulates the stability and the apoptotic function of p53 via MDM2. Mol Cell 1999; 3: 181-93.
57. Uchida C, Miwa S, Kitagawa K, Hattori T, Isobe T, Otani S, et al. Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. EMBO J 2005; 24: 160-9.
58. Tang YA, Lin RK, Tsai YT, Hsu HS, Yang YC, Chen CY, et al. MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer. Clin Cancer Res 2012; 18: 4325-33.
59. Dubs-Poterszman MC, Tocque B, Wasylyk B. MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. Oncogene 1995; 11: 2445-9.
60. Boyd MT, Vlatkovic N, Haines DS. A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2. J Biol Chem 2000; 275: 31883-90.
61. Brady M, Vlatkovic N, Boyd MT. Regulation of p53 and MDM2 activity by MTBP. Mol Cell Biol 2005; 25: 545-53.
62. Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R. MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem 2004; 279: 16000-6.
63. Xu H, Zhang Z, Li M, Zhang R. MDM2 promotes proteasomal degradation of p21Waf1 via a conformation change. J Biol Chem 2010; 285: 18407-14.
64. Malaguarnera R, Vella V, Pandini G, Sanfilippo M, Pezzino V, Vigneri R, et al. TAp73 alpha increases p53 tumor suppressor activity in thyroid cancer cells via the inhibition of Mdm2-mediated degradation. Mol Cancer Res 2008; 6: 64-77.
65. Fu W, Ma Q, Chen L, Li P, Zhang M, Ramamoorthy S, et al. MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 2009; 284: 13987-4000.
66. Gu L, Zhu N, Zhang H, Durden DL, Feng Y, Zhou M. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell 2009; 15: 363-75.
67. Manfredi JJ. The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 2010; 24: 1580-9.
68. Li Q, Lozano G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res 2013; 19: 34-41.
69. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296-9.
70. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420: 25-27.
71. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387: 299-303.
72. 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: 857-860.
73. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126-1132.
74. Thut CJ, Goodrich JA, Tjian R. Repression of p53-mediated transcription by MDM2: a dual mechanism. Genes Dev 1997; 11: 1974-1986.
75. Chi SW, Lee SH, Kim DH, Ahn MJ, Kim JS, Woo JY, et al. Structural details on mdm2-p53 interaction. J Biol Chem 2005; 280: 38795-02.
76. Poyurovsky MV, Katz C, Laptenko O, Beckerman R, Lokshin M, Ahn J, et al. The C terminus of p53 binds the N-terminal domain of MDM2. Nat Struct Mol Biol 2010; 17: 982-9.
77. Nakamura S, Roth JA, Mukhopadhyay T. Multiple lysine mutations in the C-terminal domain of p53 interfere with MDM2-dependent protein degradation and ubiquitination. Mol Cell Biol 2000, 20: 9391-98.
78. 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: 8458-67.
79. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 2000; 275: 8945-51.
80. Lee JT, Gu W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ 2010; 17: 86-92.
81. Lai Z, Ferry KV, Diamond M, Wee K, Kim YB, Ma J, et al. Human Mdm2 mediates multiple mono-ubiquitination of p53 by a mechanism requiring enzyme isomerization. J Biol Chem 2001; 276: 31357-67.
82. 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.
83. Xu GW, Mawji IA, Macrae CJ, Koch CA, Datti A, Wrana JL, et al. A high-content chemical screen identifies ellipticine as a modulator of p53 nuclear localization. Apoptosis 2008; 13: 413-22.
84. Wang X, Jiang X. Mdm2 and MdmX partner to regulate p53. FEBS Lett 2012; 586: 1390-6.
85. Marine JC, Jochemsen AG. Mdmx and Mdm2: brothers in arms? Cell Cycle 2004; 3: 900-4.
86. Marine JC, Jochemsen AG. Mdmx as an essential regulator of p53 activity. Biochem Biophys Res Commun 2005; 331: 750-60.
87. Zdzalik M, Pustelny K, Kedracka-Krok S, Huben K, Pecak A, Wladyka, B, et al. Interaction of regulators Mdm2 and Mdmx with transcription factors p53, p63 and p73. Cell Cycle 2010; 9: 4584-91.
88. Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R, et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004; 24: 5835-43.
89. Prodosmo A, Giglio S, Moretti S, Mancini F, Barbi F, Avenia N, et al. Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties. J Mol Med (Berl.) 2008; 86: 585-96.
90. Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG, et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci U S A 2011; 108: 12001-6.
91. Popowicz GM, Czarna A, Holak TA. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 2008; 7: 2441-3.
92. denBesten W, Kuo ML, Tago K, Williams RT, Sherr CJ. Ubiquitination of, and sumoylation by, the Arf tumor suppressor. Isr Med Assoc J 2006; 8: 249-51.
93. Honda R, Yasuda H. Association of p19 (ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 1999; 18: 22-7.
94. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 1998; 95: 8292-7.
95. Sherr CJ, Bertwistle D, DEN Besten W, Kuo ML, Sugimoto M, Tago K, et al. p53-dependent and-independent functions of the Arf tumor suppressor. Cold Spring Harb Symp Quant Biol 2005; 70: 129-37.
96. Weber JD, Kuo ML, Bothner B, DiGiammarino EL, Kriwacki RW, Roussel MF, et al. Cooperative signals governing ARF-mdm2 interaction and nucleolar localization of the complex. Mol Cell Biol. 2000; 20: 2517-28.
97. Korgaonkar C, Hagen J, Tompkins V, Frazier AA, Allamargot C, Quelle FW, et al. Nucleophosmin (B23) targets ARF to nucleoli and inhibits its function. Mol Cell Biol. 2005; 25: 1258-71.
98. Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, PandolfiPP, Haupt Y. The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 2003; 278: 33134-41.
99. Alsheich-Bartok O, Haupt S, Alkalay-Snir I, Saito S, Appella E, Haupt Y. PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 2008; 27: 3653-61.
100. Yang HY, Wen YY, Chen CH, Lozano G, Lee MH. 14-3-3 sigma positively regulates p53 and suppresses tumor growth. Mol Cell Biol 2003; 23: 7096-107.
101. Coutts AS, Boulahbel H, Graham A, La Thangue NB. Mdm2 targets the p53 transcription cofactor JMY for degradation. EMBO Rep 2007; 8: 84-90.
102. Coutts AS, Weston L, La Thangue NB. Actin nucleation by a transcription co-factor that links cytoskeletal events with the p53 response. Cell Cycle 2010; 9: 1511-5.
103. Bitomsky N, Hofmann TG. Apoptosis and autophagy: Regulation of apoptosis by DNA damage signaling-roles of p53, p73 and HIPK2. FEBS J 2009; 276: 6074-83.
104. D'Orazi G, Rinaldo C, Soddu S. Updates on HIPK2: a resourceful oncosuppressor for clearing cancer. J Exp Clin Cancer Res 2012; 31: 63.
105. Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu S. MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. Mol Cell 2007; 25: 739-50.
106. Puca R, Nardinocchi L, Givol D, D'Orazi G. Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells. Oncogene. 2010; 29: 4378-87.
107. Zhang Y, Lu H. Signaling to p53: ribosomal proteins find their way. Cancer Cell. 2009; 16: 369-77.
108. Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem 2004; 279: 44475-82.
109. Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA, et al. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 2003; 23: 8902-12.
110. Dai MS, Zeng SX, Jin Y, Sun XX, David L, Lu H. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Cell Biol 2004; 24: 7654-68.
111. Zhu Y, Poyurovsky MV, Li Y, Biderman L, Stahl J, Jacq X, et al. Ribosomal protein S7 is both a regulator and a substrate of MDM2. Mol Cell 2009; 35: 316-26.
112. Chen D, Zhang Z, Li M, Wang W, Li Y, Rayburn ER, et al. Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function. Oncogene 2007; 26: 5029-37.
113. Zhou X, Hao Q, Liao J, Zhang Q, Lu H. Ribosomal protein S14 unties the MDM2-p53 loop upon ribosomal stress. Oncogene 2013; 32: 388-96.
114. Zhang X, Wang W, Wang H, Wang MH, Xu W, Zhang R. Identification of ribosomal protein S25 (RPS25)-MDM2-p53 regulatory feedback loop. Oncogene. 2012. doi: 10.1038/onc.2012.289.
115. He H, Sun Y. Ribosomal protein S27L is a direct p53 target that regulates apoptosis. Oncogene 2007; 26: 2707-16.
116. Xiong X, Zhao Y, He H, Sun Y. Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis as a target, a substrate and a regulator. Oncogene 2011; 30: 1798-811.
117. Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R. RYBP stabilizes p53 by modulating MDM2. EMBO Rep 2009; 10: 166-72.
118. Su WJ, Fang JS, Cheng F, Liu C, Zhou F, Zhang J. RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development. Proc Natl Acad Sci U S A 2013; 110: 1720-5.
119. Wen W, Peng C, Kim MO, Ho Jeong C, Zhu F, Yao K, et al. Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. Oncogene 2013 doi: 10.1038/onc.2012.605. [Epub ahead of print]
120. Yogosawa S, Miyauchi Y, Honda R, Tanaka H, Yasuda H. Mammalian Numb is a target protein of Mdm2, ubiquitin ligase. Biochem Biophys Res Commun 2003; 302: 869-72.
121. Zhang XC, Chen J, Su CH, Yang HY, Lee MH. Roles for CSN5 in control of p53/MDM2 activities. J Cell Biochem 2008; 103: 1219-30.
122. Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y, Sumitomo H, et al. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell 2005; 8: 75-87.
123. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 2002; 416: 648-53.
124. Cummins JM, Vogelstein B. HAUSP is required for p53 destabilization. Cell Cycle 2004; 3: 689-92.
125. Zhang Z, Zhang R. Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation. EMBO J 2008; 27: 852-64.
126. Oliver TG, Meylan E, Chang G.P, Xue W, Burke JR, Humpton TJ, et al. Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell 2011; 43: 57-71.
127. Xiong L, Kou F, Yang Y, Wu J. A novel role for IGF-1R in p53-mediated apoptosis through translational modulation of the p53-Mdm2 feedback loop. J Cell Biol 2007; 178: 995-1007.
128. Kim H, Kwak NJ, Lee JY, Choi BH, Lim Y, Ko YJ, et al. Merlin neutralizes the inhibitory effect of Mdm2 on p53. J Biol Chem 2004; 279: 7812-7818.
129. Lo D, Lu H. Nucleostemin: Another nucleolar "Twister" of the p53-MDM2 loop. Cell Cycle 2010; 9: 3227-32.
130. Linares LK, Kiernan R, Triboulet R, Chable-Bessia C, Latreille D, Cuvier O, et al. Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2. Nat Cell Biol 2007; 9: 331-38.
131. Ray RM, Bhattacharya S, Johnson LR. Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73-and E2F1-mediated expression of PUMA and Siva-1. Apoptosis 2011; 16: 35-44.
132. Dohmesen C, Koeppel M, Dobbelstein M. Specific inhibition of Mdm2-mediated neddylation by Tip60. Cell Cycle 2008; 7: 222-31.
133. Sui G, Affar EIB, Shi Y, Brignone C, Wall NR, Yin P, et al. Yin Yang 1 is a negative regulator of p53. Cell 2004; 117: 859-72.
134. Zhang Z, Wang H, Li M, Rayburn E, Agrawal S, Zhang R. Novel MDM2 p53-independent functions identified through RNA silencing technologies. Ann N Y AcadSci 2005; 1058: 205-14.
135. Zhang Z, Wang H, Prasad G, Li M, Yu D, Bonner JA, et al. Radiosensitization by antisense anti-MDM2 mixed-backbone oligonucleotide in in vitro and in vivo human cancer models. Clin Cancer Res 2004; 10: 1263-73.
136. Zhang R, Wang H, Agrawal S. Novel antisense anti-MDM2 mixed-backbone oligonucleotides: proof of principle, in vitro and in vivo activities, and mechanisms. Curr Cancer Drug Targets 2005; 5: 43-9.
137. Lauria A, Tutone M, Ippolito M, Pantano L, Almerico AM. Molecular modeling approaches in the discovery of new drugs for anti-cancer therapy: the investigation of p53-MDM2 interaction and its inhibition by small molecules. Curr Med Chem 2010; 17: 3142-54.
138. Chène P. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer 2003; 3: 102-9.
139. Zhao J, Wang M, Chen J, Luo A, Wang X, Wu M, et al. The initial evaluation of non-peptidic small-molecule HDM2 inhibitors based on p53-HDM2 complex structure. Cancer Lett 2002; 183: 69-77.
140. Klein C, Vassilev LT. Targeting the p53-MDM2 interaction to treat cancer. Br J Cancer 2004; 91: 1415-9.
141. Vassilev LT. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 2004; 3: 419-21.
142. Elsawy KM, Verma CS, Joseph TL, Lane DP, Twarock R, Caves LS. On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study. Cell Cycle 2013; 12: 394-404.
143. Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu 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: 3933-8.
144. Buolamwini JK, Addo J, Kamath S, Patil S, Mason D, Ores M. Small molecule antagonists of the MDM2 oncoprotein as anticancer agents. Curr Cancer Drug Targets 2005; 5: 57-68.
145. Kamal A, Mohammed AA, Shaik TB. p53-Mdm2 inhibitors: patent review (2009-2010). Expert Opin Ther Pat 2012; 22: 95-105.
146. Yang Y, Ludwig RL, Jensen JP, Pierre SA, Medaglia MV, Davydov IV, et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 2005; 7: 547-59.
147. Brummelkamp TR, Fabius AW, Mullenders J, Madiredjo M, Velds A, Kerkhoven RM, et al. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nat Chem Biol 2006; 2: 202-6.
148. Brown CJ, Dastidar SG, See HY, Coomber DW, Ortiz-Lombardía M, Verma C, et al. Rational design and biophysical characterization of thioredoxin-based aptamers: insights into peptide grafting. J Mol Biol 2010; 395: 871-83.
149. Kenjo E, Asai T, Yonenaga N, Ando H, Ishii T, Hatanaka K, et al. Systemic delivery of small interfering RNA by use of targeted polycation liposomes for cancer therapy. Biol Pharm Bull 2013; 36: 287-91.
150. Yu H, Zou Y, Jiang L, Yin Q, He X, Chen L, et al. Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles. Biomaterials 2013; 34: 2738-47.
151. Qin JJ, Nag S, Voruganti S, Wang W, Zhang R. Natural product MDM2 inhibitors: anticancer activity and mechanisms of action. Curr Med Chem 2012; 19: 5705-25.
152. Wade M, Li YC, Wahl GM MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83-96.
153. Wang X. p53 regulation: teamwork between RING domains of Mdm2 and MdmX. Cell Cycle 2011; 10: 4225-9.
154. Zak K, Pecak A, Rys B, Wladyka B, Dömling A, Weber L, et al. Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present). Expert OpinTher Pat. 2013.
155. Pazgier M, Liu M, Zou G, Yuan W, Li C, Li J, et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A 2009; 106: 4665-70.
156. Chappell WH, Lehmann BD, Terrian DM, Abrams SL, Steelman LS, McCubrey JA. p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3. Cell Cycle 2012; 11: 4579-88.
157. Michaelis M, Rothweiler F, Barth S, Cinatl J, van Rikxoort M, Löschmann N, et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis 2011; 2: e243.
158. Park EJ, Choi KS, Yoo YH, Kwon TK. Nutlin-3, a small-molecule MDM2 inhibitor, sensitizes Caki cells to TRAIL-induced apoptosis through p53-mediated PUMA upregulation and ROS-mediated DR5 upregulation. Anticancer Drugs 2013; 24: 260-9.
159. Schilling D, Düwel M, Molls M, MulthoffG. Radiosensitization of wildtype p53 cancer cells by the MDM2-inhibitor PXN727 is associated with altered heat shock protein 70 (Hsp70) levels. Cell Stress Chaperones 2013; 18: 183-91.
160. Vatsyayan R, Singhal J, Nagaprashantha LD, Awasthi S, Singhal SS. Nutlin-3 enhances sorafenib efficacy in renal cell carcinoma. Mol Carcinog 2013; 52: 39-48.
161. Wang B, Fang L, Zhao H, Xiang T, Wang D. MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells. ActaBiochimBiophys Sin (Shanghai) 2012; 44: 685-91.
162. Zhuang C, Miao Z, Zhu L, Dong G, Guo Z, Wang S, et al. Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction. J Med Chem 2012; 55: 9630-42.
163. Rothweiler U, Czarna A, Krajewski M, Ciombor J, Kalinski C, Khazak V, Ross G, Skobeleva N, Weber L, Holak TA (2008) Isoquinolin-1-one inhibitors of the MDM2-p53 interaction. Chem Med Chem 3: 1118-1128.