Skip to main content
SpringerLink
Log in

Mdm2: The Ups and Downs

  • Minireview
  • Published:
Molecular Medicine Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Piette J, Neel H, Marechal V. (1997) Mdm2: keeping p53 under control. Oncogene 15: 1001–1010.

    Article  CAS  PubMed  Google Scholar 

  2. Momand J, Zambetti GP. (1997) Mdm-2: “big brother” of p53. J. Cell. Biochem. 64: 343–352.

    Article  CAS  PubMed  Google Scholar 

  3. Lozano G, Montes De Oca Luna R. (1998) MDM2 function. Biochim. Biophys. Acta 1377: M55–59.

    CAS  PubMed  Google Scholar 

  4. Cahilly-Snyder L, Yang FT, Francke U, George DL. (1987) Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat. Cell Mol. Genet. 13: 235–244.

    Article  CAS  PubMed  Google Scholar 

  5. Fakharzadeh SS, Trusko SP, George DL. (1991) Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 10: 1565–1569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Finlay CA. (1993) The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth. Mol. Cell. Biol. 13: 301–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lundgren K, Montes De Oca Luna R, McNeill YB, et al. (1997) Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes Dev. 11: 714–725.

    Article  CAS  PubMed  Google Scholar 

  8. Momand J, Jung D, Wilczynski S, Niland J. (1998) The MDM2 gene amplification database. Nucl Acids Res. 26: 3453–3459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B. (1992) Amplification of a gene encoding a p53-associated protein in human sarcomas [see comments]. Nature 358: 80–83.

    Article  CAS  PubMed  Google Scholar 

  10. Leach FS, Tokino T, Meltzer P, et al. (1993) p53 Mutation and MDM2 amplification in human soft tissue sarcomas.Cancer Res. 2231–2234.

  11. Cordon-Cardo C, Latres E, Drobnjak M, et al. (1994) Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res. 54: 794–799.

    CAS  PubMed  Google Scholar 

  12. Ladanyi M, Cha C, Lewis R, Jhanwar SC, Huvos AG, Healey JH. (1993) MDM2 gene amplification in metastatic osteosarcoma. Cancer Res. 53: 16–18.

    CAS  PubMed  Google Scholar 

  13. Shibagaki I, Tanaka H, Shimada Y, et al. (1995) p53 mutation, Murine Double Minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin. Cancer Res. 1: 769–773.

    CAS  PubMed  Google Scholar 

  14. Reifenberger G, Liu L, Ichimura K, Schmidt EE, Collins VP. (1993) Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 53: 2736–2739.

    CAS  PubMed  Google Scholar 

  15. Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VP. (1994) Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. Cancer Res. 54: 4299–4303.

    CAS  PubMed  Google Scholar 

  16. Corvi R, Savelyeva L, Breit S, et al. (1995) Nonsyntenic amplification of MDM2 and MYCN in human neuroblastoma. Oncogene 10: 1081–1086.

    CAS  PubMed  Google Scholar 

  17. Landers JE, Haines DS, Strauss JR, George DL. (1994) Enhanced translation: a novel mechanism of mdm2 oncogene overexpression identified in human tumor cells. Oncogene 9: 2745–2750.

    CAS  PubMed  Google Scholar 

  18. Landers JE, Cassel SL, George DL. (1997) Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein. Cancer Res. 57: 3562–3568.

    CAS  PubMed  Google Scholar 

  19. Wurl P, Meye A, Schmidt H, et al. (1998) High prognostic significance of Mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities. Oncogene 16: 1183–1185.

    Article  CAS  PubMed  Google Scholar 

  20. Olson DC, Marechal V, Momand J, Chen J, Romocki C, Levine AJ. (1993) Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene 8: 2353–2360.

    CAS  PubMed  Google Scholar 

  21. Haines DS, Landers JE, Engle LJ, George DL. (1994) Physical and functional interaction between wild-type p53 and mdm2 proteins. Mol. Cell. Biol. 14: 1171–1178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Marechal V, Elenbaas B, Taneyhill L, et al. (1997) Conservation of structural domains and biochemical activities of the MDM2 protein from Xenopus laevis. Oncogene 14: 1427–1433.

    Article  CAS  PubMed  Google Scholar 

  24. Elenbaas B, Dobbelstein M, Roth J, Shenk T, Levine AJ. (1996) The MDM2 oncoprotein binds specifically to RNA through its RING finger domain. Mol. Med. 2: 439–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Marechal V, Elenbaas B, Piette J, Nicolas JC, Levine AJ. (1994) The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes. Mol. Cell. Biol. 14: 7414–7420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Boddy MN, Freemont PS, Borden KL. (1994) The p53-associated protein MDM2 contains a newly characterized zinc-binding domain called the RING finger. Trends Biochem. Sci. 19: 198–199.

    Article  CAS  PubMed  Google Scholar 

  27. Roth J, Dobbelstein M, Freedman DA, Shenk T, Levine AJ. (1998) 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. 17: 554–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen L, Marechal V, Moreau J, Levine AJ, Chen J. (1997) Proteolytic cleavage of the mdm2 oncoprotein during apoptosis. J. Biol. Chem. 272: 22966–22973.

    Article  CAS  PubMed  Google Scholar 

  29. Erhardt P, Tomaselli KJ, Cooper GM. (1997) Identification of the MDM2 oncoprotein as a substrate for CPP32-like apoptotic proteases. J. Biol. Chem. 272: 15049–15052.

    Article  CAS  PubMed  Google Scholar 

  30. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69: 1237–1245.

    Article  CAS  PubMed  Google Scholar 

  31. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. (1993) Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 362: 857–860.

    Article  CAS  PubMed  Google Scholar 

  32. Chen J, Lin J, Levine AJ. (1995) Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene. Mol. Med. 1: 142–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barak Y, Juven T, Haffner R, Oren M. (1993) mdm2 expression is induced by wild-type p53 activity. EMBO J. 12: 461–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Juven T, Barak Y, Zauberman A, George DL, Oren M. (1993) Wild-type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. Oncogene 8: 3411–3416.

    CAS  PubMed  Google Scholar 

  35. Wu X, Bayle JH, Olson D, Levine AJ. (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 7: 1126–1132.

    Article  CAS  PubMed  Google Scholar 

  36. Barak Y, Gottlieb E, Juven-Gershon T, Oren M. (1994) Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev. 8: 1739–1749.

    Article  CAS  PubMed  Google Scholar 

  37. Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M. (1995) A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucl. Acids Res. 23: 2584–2592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Picksley SM, Lane DP. (1993) The p53-mdm2 autoregulatory feedback loop: a paradigm for the regulation of growth control by p53? Bioessays 15: 689–690.

    Article  CAS  PubMed  Google Scholar 

  39. Chen J, Marechal V, Levine AJ. (1993) Mapping of the p53 and mdm-2 interaction domains. Mol. Cell. Biol. 13: 4107–4114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lin J, Chen J, Elenbaas B, Levine AJ. (1994) Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev. 8: 1235–1246.

    Article  CAS  PubMed  Google Scholar 

  41. Picksley SM, Vojtesek B, Sparks A, Lane DP. (1994) Immunochemical analysis of the interaction of p53 with MDM2—fine mapping of the MDM2 binding site on p53 using synthetic peptides. Oncogene 9: 2523–2529.

    CAS  PubMed  Google Scholar 

  42. Thut CJ, Goodrich JA, Tjian R. (1997) Repression of p53-mediated transcription by MDM2: a dual mechanism. Genes Dev. 11: 1974–1986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Leng P, Brown DR, Deb S, Deb SP. (1995) Human oncoprotein MDM2 interacts with the TATA-binding protein in vitro and in vivo. Int. J. Oncology 6: 251–259.

    CAS  Google Scholar 

  44. Haupt Y, Maya R, Kazaz A, Oren M. (1997) Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299.

    Article  CAS  PubMed  Google Scholar 

  45. Kubbutat MH, Jones SN, Vousden KH. (1997) Regulation of p53 stability by Mdm2. Nature 387: 299–303.

    Article  CAS  PubMed  Google Scholar 

  46. Bottger A, Bottger V, Sparks A, Liu WL, Howard SF, Lane DP. (1997) Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr. Biol. 7: 860–869.

    Article  CAS  PubMed  Google Scholar 

  47. Honda R, Tanaka H, Yasuda H. (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420: 25–27.

    Article  CAS  PubMed  Google Scholar 

  48. Perry ME, Piette J, Zawadzki JA, Harvey D, Levine AJ. (1993) The mdm-2 gene is induced in response to UV light in a p53-dependent manner. Proc. Natl. Acad. Sci. U.S.A. 90: 11623–11627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wu L, Levine AJ. (1997) Differential regulation of the p21/WAF-1 and mdm2 genes after high-dose UV irradiation: p53-dependent and p53-independent regulation of the mdm2 gene. Mol. Med. 3: 441–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Saucedo LJ, Carstens BP, Seavey SE, Albee LD, Perry ME. (1998) Regulation of transcriptional activation of mdm2 gene by p53 in response to UV radiation. Cell Growth Differ. 9: 119–130.

    CAS  PubMed  Google Scholar 

  51. Chen CY, Oliner JD, Zhan Q, Fornace AJ, Vogelstein B, Kastan MB. (1994) Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc. Natl. Acad. Sci. U.S.A. 91: 2684–2688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Price BD, Park SJ. (1994) DNA damage increases the levels of MDM2 messenger RNA in wtp53 human cells. Cancer Res. 54: 896–899.

    CAS  PubMed  Google Scholar 

  53. Chang YC, Lee YS, Tejima T, et al. (1998) mdm2 and bax, downstream mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. Cell Growth Differ. 9: 79–84.

    CAS  PubMed  Google Scholar 

  54. Kussie PH, Gorina S, Marechal V, et al. (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274: 948–953.

    Article  CAS  PubMed  Google Scholar 

  55. Marston NJ, Jenkins JR, Vousden KH. (1995) Oligomerisation of full length p53 contributes to the interaction with mdm2 but not HPV E6. Oncogene 10: 1709–1715.

    CAS  PubMed  Google Scholar 

  56. Kubbutat M, Ludwig RL, Ashcroft M, Vousden KH. (1998) Regulation of Mdm2-directed degradation by the C terminus of p53. Mol. Cell. Biol. 18: 5690–5698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Prives C. (1998) Signaling to p53: breaking the MDM2-p53 circuit. Cell 95: 5–8.

    Article  CAS  PubMed  Google Scholar 

  58. Freedman DA, Levine AJ. (1998) Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol. Cell. Biol. 18: 7288–7293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen J, Wu X, Lin J, Levine AJ. (1996) mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Mol. Cell. Biol. 16: 2445–2452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Haupt Y, Barak Y, Oren M. (1996) Cell type-specific inhibition of p53-mediated apoptosis by mdm2. EMBO J. 15: 1596–1606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Momand J, Zambetti GP. (1996) Analysis of the proportion of p53 bound to mdm-2 in cells with defined growth characteristics. Oncogene 12: 2279–2289.

    CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. Shieh SY, Ikeda M, Taya Y, Prives C. (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91: 325–334.

    Article  CAS  PubMed  Google Scholar 

  65. Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E, Kastan MB. (1997) DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 11: 3471–3481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Banin S, Moyal L, Shieh S, et al. (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281: 1674–1677.

    Article  CAS  PubMed  Google Scholar 

  67. Canman CE, Lim DS, Cimprich KA, et al. (1998) Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53. Science 281: 1677–1679.

    Article  CAS  PubMed  Google Scholar 

  68. Woo RA, McLure KG, Lees-Miller SP, Rancourt DE, Lee PW. (1998) DNA-dependent protein kinase acts upstream of p53 in response to DNA damage. Nature 394: 700–704.

    Article  CAS  PubMed  Google Scholar 

  69. Barak Y, Oren M. (1992) Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest. EMBO J. 11: 2115–2121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Guerra B, Gotz C, Wagner P, Montenarh M, Issinger OG. (1997) The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation. Oncogene 14: 2683–2688.

    Article  CAS  PubMed  Google Scholar 

  71. Mayo LD, Turchi JJ, Berberich SJ. (1997) Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res. 57: 5013–5016.

    CAS  PubMed  Google Scholar 

  72. Henning W, Rohaly G, Kolzau T, Knippschild U, Maacke H, Deppert W. (1997) MDM2 is a target of simian virus 40 in cellular transformation and during lytic infection. J. Virol. 71: 7609–7618.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bottger V, Bottger A, Howard SF, et al. (1996) Identification of novel mdm2 binding peptides by phage display. Oncogene 13: 2141–2147.

    CAS  PubMed  Google Scholar 

  74. Bottger A, Bottger V, Garcia EC, et al. (1997) Molecular characterization of the hdm2-p53 interaction. J. Mol. Biol. 269: 744–756.

    Article  CAS  PubMed  Google Scholar 

  75. Chen L, Agrawal S, Zhou W, Zhang R, Chen J. (1998) Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage. Proc. Natl. Acad. Sci. U.S.A. 95: 195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Blaydes JP, Wynford-Thomas D. (1998) The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2. Oncogene 16: 3317–3322.

    Article  CAS  PubMed  Google Scholar 

  78. Dahl AM, Beverley PC, Stauss HJ. (1996) A synthetic peptide derived from the tumor-associated protein mdm2 can stimulate autoreactive, high avidity cytotoxic T lymphocytes that recognize naturally processed protein. J. Immunol 157: 239–246.

    CAS  PubMed  Google Scholar 

  79. Xiao ZX, Chen J, Levine AJ, et al. (1995) Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature 375: 694–698.

    Article  CAS  PubMed  Google Scholar 

  80. Martin K, Trouche D, Hagemeier C, Sorensen TS, La Thangue N, Kouzarides T. (1995) Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature 375: 691–694.

    Article  CAS  PubMed  Google Scholar 

  81. Hsieh JK, Fredersdorf S, Kouzarides T, Martin K, Lu X. (1997) E2F1-induced apoptosis requires DNA binding but not transactivation and is inhibited by the retinoblastoma protein through direct interaction. Genes Dev. 11: 1840–1852.

    Article  CAS  PubMed  Google Scholar 

  82. Kowalik TF, DeGregori J, Leone G, Jakoi L, Nevins JR. (1998) E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ. 9: 113–118.

    CAS  PubMed  Google Scholar 

  83. O’Connor DJ, Lam EW, Griffin S, et al. (1995) Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DPI. EMBO J. 14: 6184–6192.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Sorensen TS, Girling R, Lee CW, Gannon J, Bandara LR, La Thangue N. (1996) Functional interaction between DP-1 and p53. Mol. Cell. Biol. 16: 5888–5895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Juven-Gershon T, Shifman O, Unger T, Elkeles A, Haupt Y, Oren M. (1998) The Mdm2 oncoprotein interacts with the cell fate regulator numb. Mol. Cell. Biol. 18: 3974–3982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zeng X, Chen L, Jost CA, et al. Mdm2 suppresses p73 function without promoting p73 degradation. Mol. Cell. Biol. (in press).

  87. 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.

    Article  CAS  PubMed  Google Scholar 

  88. Pomerantz J, Schreiber AN, Liegeois NJ, et al. (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 92: 713–723.

    Article  CAS  PubMed  Google Scholar 

  89. 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.

    Article  CAS  PubMed  Google Scholar 

  90. 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. U.S.A. 95: 8292–8297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stott FJ, Bates S, James MC, et al. (1998) The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 17: 5001–5014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bates S, Phillips AC, Clark PA, et al. (1998) p14ARF links the tumour suppressors RB and p53. Nature 395: 124–125.

    Article  CAS  PubMed  Google Scholar 

  93. de-Stanchina E, McCurrach ME, Zindy F, et al. (1998) E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 12: 2434–2442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zindy F, Eischen CM, Randle DH, et al. (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12: 2424–2433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Palmero I, Pantoja C, Serrano M. (1998) p19ARF links the tumour suppressor p53 to Ras. Nature 395: 125–126.

    Article  CAS  PubMed  Google Scholar 

  96. Grossman SR, Perez M, Kung AL, et al. (1998) p300/MDM2 complexes participate in MDM2-mediated p53 degradation. Mol. Cell 2: 405–415.

    Article  CAS  PubMed  Google Scholar 

  97. Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM. (1997) Binding and modulation of p53 by p300/CBP coactivators. Nature 387: 823–827.

    Article  CAS  PubMed  Google Scholar 

  98. Gu W, Shi XL, Roeder RG. (1997) Synergistic activation of transcription by CBP and p53. Nature 387: 819–823.

    Article  CAS  PubMed  Google Scholar 

  99. Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K. (1997) Recruitment of p300/CBP in p53-dependent signal pathways. Cell 89: 1175–1184.

    Article  CAS  PubMed  Google Scholar 

  100. Scolnick DM, Chehab NH, Stavridi ES, et al. (1997) CREB-binding protein and p300/CBP-as-sociated factor are transcriptional coactivators of the p53 tumor suppressor protein. Cancer Res. 57: 3693–3696.

    CAS  PubMed  Google Scholar 

  101. Thomas A, White E. (1998) Suppression of the p300-dependent mdm2 negative-feedback loop induces the p53 apoptotic function. Genes Dev. 12: 1975–1985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. McMasters KM, Montes De Oca Luna R, Pena JR, Lozano G. (1996) mdm2 deletion does not alter growth characteristics of p53-deficient embryo fibroblasts. Oncogene 13: 1731–1736.

    CAS  PubMed  Google Scholar 

  103. Jones SN, Sands AT, Hancock AR, et al. (1996) The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2. Proc. Natl Acad. Sci. U.S.A. 93: 14106–14111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dubs-Poterszman M, 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.

    CAS  PubMed  Google Scholar 

  105. Sun P, Dong P, Dai K, Hannon GJ, Beach D. (1998) p53-independent role of MDM2 in TGFβ1 resistance. Science 282: 2270–2272.

    Article  CAS  PubMed  Google Scholar 

  106. Shvarts A, Steegenga WT, Riteco N, et al. (1996) MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 15: 5349–5357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Leveillard T, Gorry P, Niederreither K, Wasylyk B. (1998) MDM2 expression during mouse embryogenesis and the requirement of p53. Mech. Dev. 74: 189–193.

    Article  CAS  PubMed  Google Scholar 

  108. Fiddler TA, Smith L, Tapscott SJ, Thayer MJ. (1996) Amplification of MDM2 inhibits MyoD-mediated myogenesis. Mol. Cell. Biol. 16: 5048–5057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shvarts A, Bazuine M, Dekker P, et al. (1997) Isolation and identification of the human homolog of a new p53-binding protein, Mdmx. Genomics 43: 34–42.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratory is supported by grant RO1 CA 40099 from the National Cancer Institute, The Israel Science Foundation, Israel Academy of Sciences and Humanities—Centers of Excellence Program, the Israel-USA Binational Science Foundation, the German-Israeli Foundation for Scientific Research and Development, and the Leo and Julia Forchheimer Center for Molecular Genetics.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology, Weizmann Institute of Science, 76100, Rehovot, Israel

    Tamar Juven-Gershon &  Moshe Oren

Authors
  1. Tamar Juven-Gershon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moshe Oren
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juven-Gershon, T., Oren, M. Mdm2: The Ups and Downs. Mol Med 5, 71–83 (1999). https://doi.org/10.1007/BF03402141

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03402141

Keywords

Search

Navigation