The mdm network and its regulation of p53 activities: A rheostat of cancer risk

Human Mutation

Volumn 35, Issue 6, 2014, Pages 728-737

  Eischen, Christine M ^a   Lozano, Guillermina ^b  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

Mdm2; Mdm4; Mouse models; P53; TCGA; TP53; Trp53

Indexed keywords

MUTANT PROTEIN; PROTEIN MDM2; PROTEIN MDMX; PROTEIN P53; TUMOR SUPPRESSOR PROTEIN; MDM2 PROTEIN, HUMAN; MDM4 PROTEIN, HUMAN; NUCLEAR PROTEIN; ONCOPROTEIN; TP53 PROTEIN, HUMAN;

CANCER RISK; CELL CYCLE ARREST; CELL DEATH; GENE INACTIVATION; GENETIC RISK; HAPLOINSUFFICIENCY; HUMAN; MISSENSE MUTATION; MUTANT; NEOPLASM; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL CYCLE CHECKPOINT; CELL PROLIFERATION; GENETIC TRANSCRIPTION; GENETICS; MOUSE; PATHOLOGY; RISK FACTOR;

MUS;

ANIMALS; CELL CYCLE CHECKPOINTS; CELL DEATH; CELL PROLIFERATION; HUMANS; MICE; NEOPLASMS; NUCLEAR PROTEINS; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-MDM2; RISK FACTORS; TRANSCRIPTION, GENETIC; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84901193949     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22524     Document Type: Review

References (144)

1. Abida WM, Gu W. 2008. p53-dependent and p53-independent activation of autophagy by ARF. Cancer Res 68:352-357.
2. Alt JR, Bouska A, Fernandez MR, Cerny RL, Xiao H, Eischen CM. 2005. Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair. J Biol Chem 280:18771-18781.
3. Alt JR, Greiner TC, Cleveland JL, Eischen CM. 2003. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J 22:1442-1450.
4. Aziz MH, Shen H, Maki CG. 2011. Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene 30:4678-4686.
5. Balmain A, Gray J, Ponder B. 2003. The genetics and genomics of cancer. Nat Genet 33(Suppl):238-244.
6. Barboza JA, Liu G, Ju Z, El-Naggar AK, Lozano G. 2006. p21 delays tumor onset by preservation of chromosomal stability. Proc Natl Acad Sci USA 103:19842-19847.
7. Birch JM, Blair V, Kelsey AM, Evans DG, Harris M, Tricker KJ, Varley JM. 1998. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene 17:1061-1068.
8. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, et al. 2004. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591-602.
9. Bond GL, Levine AJ. 2007. A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 26:1317-1323.
10. Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L, Chompret A, Bressac-de Paillerets B, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T. 2006. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet 43:531-533.
11. Bouska A, Lushnikova T, Plaza S, Eischen CM. 2008. Mdm2 promotes genetic instability and transformation independent of p53. Mol Cell Biol 28:4862-4874.
12. Brown DR, Thomas CA, Deb SP. 1998. The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis. EMBO J 17:2513-2525.
13. Capoulade C, Bressac-de Paillerets B, Lefrere I, Ronsin M, Feunteun J, Tursz T, Wiels J. 1998. Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells. Oncogene 16:1603-1610.
14. Carrillo AM, Bouska A, Arrate MP, Eischen CM. In press. Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene. [Accepted].
15. Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, Li YQ, Tarapore P, Fukasawa K. 1999. Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 18:1935-1944.
16. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, et al. 2012. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401-404.
17. Chavez-Reyes A, Parant JM, Amelse LL, de Oca Luna RM, Korsmeyer SJ, Lozano G. 2003. Switching mechanisms of cell death in mdm2- and mdm4-null mice by deletion of p53 downstream targets. Cancer Res 63:8664-8669.
18. Chen D, Shan J, Zhu WG, Qin J, Gu W. 2010. Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature 464:624-627.
19. Chen Z, Carracedo A, Lin HK, Koutcher JA, Behrendt N, Egia A, Alimonti A, Carver BS, Gerald W, Teruya-Feldstein J, Loda M, Pandolfi PP. 2009. Differential p53-independent outcomes of p19(Arf) loss in oncogenesis. Sci Signal 2:ra44.
20. Cheng Q, Chen J. 2011. The phenotype of MDM2 auto-degradation after DNA damage is due to epitope masking by phosphorylation. Cell Cycle 10:1162-1166.
21. Cho Y, Gorina S, Jeffrey PD, Pavletich NP. 1994. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346-355.
22. Cordon-Cardo C, Latres E, Drobnjak M, Oliva MR, Pollack D, Woodruff JM, Marechal V, Chen J, Brennan MF, Levine AJ. 1994. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 54:794-799.
23. Crook T, Vousden KH. 1992. Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens. EMBO J 11:3935-3940.
24. Cummins JM, Rago C, Kohli M, Kinzler KW, Lengauer C, Vogelstein B. 2004. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 428:1 p following 486.
25. Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R, de Graaf P, Francoz S, Gasparini P, Gobbi A, Helin K, Pelicci PG, et al. 2004. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 24:5835-5843.
26. De Clercq S, Gembarska A, Denecker G, Maetens M, Naessens M, Haigh K, Haigh JJ, Marine JC. 2010. Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. Mol Cell Biol 30:5394-5405.
27. Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C, Levine AJ. 1993. Gain of function mutations in p53. Nat Genet 4:42-46.
28. Dubs-Poterszman MC, Tocque B, Wasylyk B. 1995. MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. Oncogene 11:2445-2449.
29. Eischen CM. 2011. Decreased Mdm2 levels after DNA damage: antibody masking or protein degradation? Cell Cycle 10:1347.
30. Eischen CM, Alt JR, Wang P. 2004. Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development. Oncogene 23:8931-8940.
31. Eischen CM, Boyd K. 2012. Decreased Mdm2 expression inhibits tumor development and extends survival independent of Arf and dependent on p53. PLoS One 7:e46148.
32. Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL. 1999. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13:2658-2669.
33. Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, Herman JG. 2000. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 60:129-133.
34. Fang M, Simeonova I, Bardot B, Lejour V, Jaber S, Bouarich-Bourimi R, Morin A, Toledo F. 2013. Mdm4 loss in mice expressing a p53 hypomorph alters tumor spectrum without improving survival. Oncogene. doi:10.1038/onc.2013.62
35. Finch RA, Donoviel DB, Potter D, Shi M, Fan A, Freed DD, Wang CY, Zambrowicz BP, Ramirez-Solis R, Sands AT, Zhang N. 2002. mdmx is a negative regulator of p53 activity in vivo. Cancer Res 62:3221-3225.
36. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, et al. 2013. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:pl1.
37. Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, et al. 2012. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18:1239-1247.
38. Giglio S, Mancini F, Gentiletti F, Sparaco G, Felicioni L, Barassi F, Martella C, Prodosmo A, Iacovelli S, Buttitta F, Farsetti A, Soddu S, et al. 2005. Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization. Cancer Res 65:9687-9694.
39. Gunther T, Schneider-Stock R, Rys J, Niezabitowski A, Roessner A. 1997. p53 gene mutations and expression of p53 and mdm2 proteins in invasive breast carcinoma. A comparative analysis with clinico-pathological factors. J Cancer Res Clin Oncol 123:388-394.
40. Hamroun D, Kato S, Ishioka C, Claustres M, Beroud C, Soussi T. 2006. The UMD TP53 database and website: update and revisions. Hum Mutat 27:14-20.
41. Han X, Garcia-Manero G, McDonnell TJ, Lozano G, Medeiros LJ, Xiao L, Rosner G, Nguyen M, Fernandez M, Valentin-Vega YA, Barboza J, Jones DM, et al. 2007. HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target. Mod Pathol 20:54-62.
42. Haupt Y, Maya R, Kazaz A, Oren M. 1997. Mdm2 promotes the rapid degradation of p53. Nature 387:296-299.
43. Heinmoller E, Dietmaier W, Zirngibl H, Heinmoller P, Scaringe W, Jauch KW, Hofstadter F, Ruschoff J. 2000. Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. Am J Pathol 157:83-92.
44. Honda R, Tanaka H, Yasuda H. 1997. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25-27.
45. Hsiao M, Low J, Dorn E, Ku D, Pattengale P, Yeargin J, Haas M. 1994. Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness. Am J Pathol 145:702-714.
46. Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG, Zuo Y, Kawai H, Shadfan M, Ganapathy S, Yuan ZM. 2011. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci USA 108:12001-12006.
47. Hustinx SR, Leoni LM, Yeo CJ, Brown PN, Goggins M, Kern SE, Hruban RH, Maitra A. 2005. Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol 18:959-963.
48. Hwang SJ, Cheng LS, Lozano G, Amos CI, Gu X, Strong LC. 2003. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum Genet 113:238-243.
49. Jackson MW, Lindstrom MS, Berberich SJ. 2001. MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. J Biol Chem 276:25336-25341.
50. Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A. 1998. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA 95:15608-15612.
51. Jones SN, Roe AE, Donehower LA, Bradley A. 1995. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378:206-208.
52. Kamijo T, Bodner S, van de Kamp E, Randle DH, Sherr CJ. 1999. Tumor spectrum in ARF-deficient mice. Cancer Res 59:2217-2222.
53. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. 1998. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 95:8292-8297.
54. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ. 1997. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649-659.
55. Kato MV, Shimizu T, Ishizaki K, Kaneko A, Yandell DW, Toguchida J, Sasaki MS. 1996. Loss of heterozygosity on chromosome 17 and mutation of the p53 gene in retinoblastoma. Cancer Lett 106:75-82.
56. Kim WY, Sharpless NE. 2006. The regulation of INK4/ARF in cancer and aging. Cell 127:265-275.
57. Knappskog S, Bjornslett M, Myklebust LM, Huijts PE, Vreeswijk MP, Edvardsen H, Guo Y, Zhang X, Yang M, Ylisaukko-Oja SK, Alhopuro P, Arola J, et al. 2011. The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. Cancer Cell 19:273-282.
58. Kon N, Zhong J, Kobayashi Y, Li M, Szabolcs M, Ludwig T, Canoll PD, Gu W. 2011. Roles of HAUSP-mediated p53 regulation in central nervous system development. Cell Death Differ 18:1366-1375.
59. Kubbutat MH, Jones SN, Vousden KH. 1997. Regulation of p53 stability by Mdm2. Nature 387:299-303.
60. Landers JE, Haines DS, Strauss JF 3rd, George DL. 1994. Enhanced translation: a novel mechanism of mdm2 oncogene overexpression identified in human tumor cells. Oncogene 9:2745-2750.
61. Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, El-Naggar AK, Lozano G. 2004. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861-872.
62. Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C, Teunisse A, Lam S, Ramos Y, Mohan A, Johnson D, Wilson M, et al. 2006. Inactivation of the p53 pathway in retinoblastoma. Nature 444:61-66.
63. Lenos K, Grawenda AM, Lodder K, Kuijjer ML, Teunisse AF, Repapi E, Grochola LF, Bartel F, Hogendoorn PC, Wuerl P, Taubert H, Clinton-Jansen AM, et al. 2012. Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer. Cancer Res 72:4074-4084.
64. Leventaki V, Rodic V, Tripp SR, Bayerl MG, Perkins SL, Barnette P, Schiffman JD, Miles RR. 2012. TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases. Br J Haematol 158:763-771.
65. Li C, Finkelstein D, Sherr CJ. 2013. Arf tumor suppressor and miR-205 regulate cell adhesion and formation of extraembryonic endoderm from pluripotent stem cells. Proc Natl Acad Sci USA 110:E1112-E1121.
66. Li M, Brooks CL, Kon N, Gu W. 2004. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell 13:879-886.
67. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W. 2002. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416:648-653.
68. Li Q, Lozano G. 2013. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res 19:34-41.
69. Li X, Gilkes D, Li B, Cheng Q, Pernazza D, Lawrence H, Lawrence N, Chen J. 2012. Abnormal MDMX degradation in tumor cells due to ARF deficiency. Oncogene 31:3721-3732.
70. Linke K, Mace PD, Smith CA, Vaux DL, Silke J, Day CL. 2008. Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ 15:841-848.
71. Liu G, Wheatley-Price P, Zhou W, Park S, Heist RS, Asomaning K, Wain JC, Lynch TJ, Su L, Christiani DC. 2008. Genetic polymorphisms of MDM2, cumulative cigarette smoking and nonsmall cell lung cancer risk. Int J Cancer 122:915-918.
72. Liu L, Fan L, Fang C, Zou ZJ, Yang S, Zhang LN, Li JY, Xu W. 2012. S-MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia. Cancer Sci 103:2056-2063.
73. Llanos S, Clark PA, Rowe J, Peters G. 2001. Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nat Cell Biol 3:445-452.
74. Lozano G. 2007. The oncogenic roles of p53 mutants in mouse models. Curr Opin Genet Dev 17:66-70.
75. Lu ML, Wikman F, Orntoft TF, Charytonowicz E, Rabbani F, Zhang Z, Dalbagni G, Pohar KS, Yu G, Cordon-Cardo C. 2002. Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods. Clin Cancer Res 8:171-179.
76. Ludwig RL, Bates S, Vousden KH. 1996. Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol 16:4952-4960.
77. Lundgren K, Montes de Oca Luna R, McNeill YB, Emerick EP, Spencer B, Barfield CR, Lozano G, Rosenberg MP, Finlay CA. 1997. Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes Dev 11:714-725.
78. Lushnikova T, Bouska A, Odvody J, Dupont WD, Eischen CM. 2011. Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression. Oncogene 30:4622-4631.
79. Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De Marzo A, Cameron JL, Yeo CJ, Hruban RH. 2003. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 16:902-912.
80. Matijasevic Z, Krzywicka-Racka A, Sluder G, Jones SN. 2008a. MdmX regulates transformation and chromosomal stability in p53-deficient cells. Cell Cycle 7:2967-2973.
81. Matijasevic Z, Steinman HA, Hoover K, Jones SN. 2008b. MdmX promotes bipolar mitosis to suppress transformation and tumorigenesis in p53-deficient cells and mice. Mol Cell Biol 28:1265-1273.
82. Maya R, Oren M. 2000. Unmasking of phosphorylation-sensitive epitopes on p53 and Mdm2 by a simple Western-phosphatase procedure. Oncogene 19:3213-3215.
83. McDonnell TJ, Montes de Oca Luna R, Cho S, Amelse LL, Chavez-Reyes A, Lozano G. 1999. Loss of one but not two mdm2 null alleles alters the tumour spectrum in p53 null mice. J Pathol 188:322-328.
84. Meek DW, Hupp TR. 2010. The regulation of MDM2 by multisite phosphorylation-opportunities for molecular-based intervention to target tumours? Semin Cancer Biol 20:19-28.
85. Melo AN, Eischen CM. 2012. Protecting the genome from mdm2 and mdmx. Genes Cancer 3:283-290.
86. Mendrysa SM, McElwee MK, Michalowski J, O'Leary KA, Young KM, Perry ME. 2003. mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol 23:462-472.
87. Mendrysa SM, O'Leary KA, McElwee MK, Michalowski J, Eisenman RN, Powell DA, Perry ME. 2006. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 20:16-21.
88. Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H, Abraham TE, Dirks RW, Jochemsen AG. 2005. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell 18:565-576.
89. Michaelis M, Rothweiler F, Barth S, Cinatl J, van Rikxoort M, Loschmann N, Voges Y, Breitling R, von Deimling A, Rodel F, Weber K, Fehse B, et al. 2011. 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 2:e243.
90. Midgley CA, Lane DP. 1997. p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. Oncogene 15:1179-1189.
91. Migliorini D, Lazzerini Denchi E, Danovi D, Jochemsen A, Capillo M, Gobbi A, Helin K, Pelicci PG, Marine JC. 2002. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol 22:5527-5538.
92. Montes de Oca Luna R, Wagner DS, Lozano G. 1995. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378:203-206.
93. Moore L, Venkatachalam S, Vogel H, Watt JC, Wu CL, Steinman H, Jones SN, Donehower LA. 2003. Cooperativity of p19ARF, Mdm2, and p53 in murine tumorigenesis. Oncogene 22:7831-7837.
94. O'Leary KA, Mendrysa SM, Vaccaro A, Perry ME. 2004. Mdm2 regulates p53 independently of p19(ARF) in homeostatic tissues. Mol Cell Biol 24:186-191.
95. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B. 1992. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358:80-83.
96. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, Crowley D, Jacks T. 2004. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119:847-860.
97. Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P. 2002. The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19:607-614.
98. Olivier M, Hollstein M, Hainaut P. 2010. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2:a001008.
99. Onel K, Cordon-Cardo C. 2004. MDM2 and prognosis. Mol Cancer Res 2:1-8.
100. Pant V, Xiong S, Iwakuma T, Quintas-Cardama A, Lozano G. 2011. 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 108:11995-2000.
101. Pant V, Xiong S, Jackson JG, Post SM, Abbas HA, Quintas-Cardama A, Hamir AN, Lozano G. 2013. The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity. Genes Dev 27:1857-1867.
102. Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, Jochemsen AG, Lozano G. 2001. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet 29:92-95.
103. Peng Y, Chen L, Li C, Lu W, Agrawal S, Chen J. 2001. Stabilization of the MDM2 oncoprotein by mutant p53. J Biol Chem 276:6874-6878.
104. Post SM, Quintas-Cardama A, Pant V, Iwakuma T, Hamir A, Jackson JG, Maccio DR, Bond GL, Johnson DG, Levine AJ, Lozano G. 2010. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18:220-230.
105. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. 1995. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83:993-1000.
106. Ramos YF, Stad R, Attema J, Peltenburg LT, van der Eb AJ, Jochemsen AG. 2001. Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res 61:1839-1842.
107. Rayburn E, Zhang R, He J, Wang H. 2005. MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 5:27-41.
108. Resnick MA, Inga A. 2003. Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc Natl Acad Sci USA 100:9934-9939.
109. Riemenschneider MJ, Buschges R, Wolter M, Reifenberger J, Bostrom J, Kraus JA, Schlegel U, Reifenberger G. 1999. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res 59:6091-6096.
110. Riley MF, Lozano G. 2012. The many faces of MDM2 binding partners. Genes Cancer 3:226-239.
111. Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, Kern SE. 1997. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 57:1731-1734.
112. Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomaki K, Pruntel R, Verhoef S, Van't Veer LJ. 2007. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15:110-114.
113. Sanchez-Cespedes M, Reed AL, Buta M, Wu L, Westra WH, Herman JG, Yang SC, Jen J, Sidransky D. 1999. Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. Oncogene 18:5843-5839.
114. Schmidt MK, Reincke S, Broeks A, Braaf LM, Hogervorst FB, Tollenaar RA, Johnson N, Fletcher O, Peto J, Tommiska J, Blomqvist C, Nevanlinna HA, et al. 2007. Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. Cancer Res 67:9584-9590.
115. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW. 1999. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev 13:2670-2677.
116. Sherr CJ. 2006. Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 6:663-673.
117. Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M, van Ham RC, van der Houven van Oordt W, Hateboer G, van der Eb AJ, Jochemsen AG. 1996. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 15:5349-5357.
118. Sigal A, Rotter V. 2000. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60:6788-6793.
119. Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J. 1996. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 2:912-917.
120. Smeds J, Berggren P, Ma X, Xu Z, Hemminki K, Kumar R. 2002. Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF)) and p53 genes are major targets for inactivation. Carcinogenesis 23:645-655.
121. Suda T, Yoshihara M, Nakamura Y, Sekiguchi H, Godai TI, Sugano N, Tsuchida K, Shiozawa M, Sakuma Y, Tsuchiya E, Kameda Y, Akaike M, et al. 2011. Rare MDM4 gene amplification in colorectal cancer: the principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable. Oncol Rep 26:49-54.
122. Suh YA, Post SM, Elizondo-Fraire AC, Maccio DR, Jackson JG, El-Naggar AK, Van Pelt C, Terzian T, Lozano G. 2011. Multiple stress signals activate mutant p53 in vivo. Cancer Res 71:7168-7175.
123. Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, Van Pelt CS, Lozano G. 2008. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 22:1337-1344.
124. Terzian T, Wang Y, Van Pelt CS, Box NF, Travis EL, Lozano G. 2007. Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol Cell Biol 27:5479-5485.
125. Valentin-Vega YA, Barboza JA, Chau GP, El-Naggar AK, Lozano G. 2007. High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas. Hum Pathol 38:1553-1562.
126. Varley JM, Thorncroft M, McGown G, Appleby J, Kelsey AM, Tricker KJ, Evans DG, Birch JM. 1997. A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. Oncogene 14:865-871.
127. Venkatachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D, Donehower LA. 1998. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J 17:4657-4667.
128. Vogelstein B, Kinzler KW. 1992. Carcinogens leave fingerprints. Nature 355:209-210.
129. Vogelstein B, Lane D, Levine AJ. 2000. Surfing the p53 network. Nature 408:307-310.
130. Vousden KH, Prives C. 2009. Blinded by the light: the growing complexity of p53. Cell 137:413-431.
131. Wade M, Li YC, Wahl GM. 2013. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13:83-96.
132. Wang P, Greiner TC, Lushnikova T, Eischen CM. 2006. Decreased Mdm2 expression inhibits tumor development induced by loss of ARF. Oncogene 25:3708-3718.
133. Wang P, Lushnikova T, Odvody J, Greiner TC, Jones SN, Eischen CM. 2008. Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells. Oncogene 27:1590-1598.
134. Wang X, Arooz T, Siu WY, Chiu CH, Lau A, Yamashita K, Poon RY. 2001. MDM2 and MDMX can interact differently with ARF and members of the p53 family. FEBS Lett 490:202-208.
135. Wang Y, Suh YA, Fuller MY, Jackson JG, Xiong S, Terzian T, Quintas-Cardama A, Bankson JA, El-Naggar AK, Lozano G. 2011. Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation. J Clin Invest 121:893-904.
136. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP. 2000. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev 14:2358-2365.
137. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. 1999. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1:20-26.
138. Wilkening S, Bermejo JL, Hemminki K. 2007. MDM2 SNP309 and cancer risk: a combined analysis. Carcinogenesis 28:2262-2267.
139. Xiong S, Pant V, Suh YA, Van Pelt CS, Wang Y, Valentin-Vega YA, Post SM, Lozano G. 2010. Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res 70:7148-7154.
140. Yarden RI, Friedman E, Metsuyanim S, Olender T, Ben-Asher E, Papa MZ. 2008. MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. Breast Cancer Res Treat 111:497-504.
141. Zhang T, Prives C. 2001. Cyclin a-CDK phosphorylation regulates MDM2 protein interactions. J Biol Chem 276:29702-29710.
142. Zhang Y, Xiong Y, Yarbrough WG. 1998. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725-734.
143. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF. 1998. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12:2424-2433.
144. Zou M, Shi Y, al-Sedairy S, Hussain SS, Farid NR. 1995. The expression of the MDM2 gene, a p53 binding protein, in thyroid carcinogenesis. Cancer 76:314-318.