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Gene Review

Mdm2  -  transformed mouse 3T3 cell double minute 2

Mus musculus

Synonyms: 1700007J15Rik, AA415488, Double minute 2 protein, E3 ubiquitin-protein ligase Mdm2, Mdm-2, ...
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Disease relevance of Mdm2


High impact information on Mdm2

  • Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53 [6].
  • Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction [7].
  • In primary cells, Raf also activates the Mdm2 inhibitor p19ARF [7].
  • During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss [8].
  • Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein [9].

Chemical compound and disease context of Mdm2

  • In this study, we show that hypoxia induces down-regulation of Mdm2 as well as serine 15 phosphorylation and nuclear accumulation of p53 in cultured cortical neurons from E16 mice [10].
  • Our data indicate that Mdm2 inhibitors may be an effective means of selectively targeting colon cancers that retain a sequence-normal p53 gene while sparing normal tissue and that the AOM model is an appropriate model for the preclinical development of these drugs [11].

Biological context of Mdm2

  • Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis [12].
  • Additionally, Mdm2 and Mdm4 had a gene dosage effect, because loss of three of the four Mdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone [1].
  • In addition, activation of PKB correlated with Mdm2 phosphorylation and stability in a variety of human tumor cells [13].
  • Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair [14].
  • Mice deleted for either Mdm2 or Mdm4 die during embryogenesis, and the developmental lethality of either mouse model can be rescued by concomitant deletion of p53 [15].

Anatomical context of Mdm2


Associations of Mdm2 with chemical compounds

  • In order to address the issue of how these modifications might regulate Mdm2 function, putative phosphorylation sites within this domain were substituted, individually or in pairs, with alanine residues [20].
  • Cellular localization and co-immunoprecipitation experiments using a cell line derived from an AOM-induced colon tumor (AJ02-NM(0) cells) pointed to constitutively expressed Mdm2 as being an important negative regulator of p53 in these cells [11].
  • We tested the response of AJ02-NM(0) cells to the recently developed Mdm2 inhibitor, Nutlin-3 [11].
  • ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage [21].
  • A role for the polyproline domain of p53 in its regulation by Mdm2 [22].

Physical interactions of Mdm2

  • The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression [23].

Enzymatic interactions of Mdm2

  • Recently, B56gamma subunit-containing PP2A holoenzymes have shown to dephosphorylate Mdm2, a negative regulator of p53 [2].

Co-localisations of Mdm2


Regulatory relationships of Mdm2

  • Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo [25].
  • A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance [2].
  • Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis [26].
  • p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons [10].

Other interactions of Mdm2

  • The protein encoded by the murine double minute 2 (Mdm2) gene inactivates the function of the tumor suppressor p53 [18].
  • Constitutive overexpression of Mdm2 and Cdk4 mRNAs was found, which might have contributed to the loss of G1 arrest [27].
  • Recent data show that cyclin G1 can regulate the levels of p53 by a mechanism that involves dephosphorylation of Mdm2 by protein phosphatase 2A [28].
  • Mice lacking Mdm2 in the heart were embryonic lethal and showed defects at the time recombination occurred [29].
  • Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation [30].

Analytical, diagnostic and therapeutic context of Mdm2

  • Western blot analyses revealed that irradiated COS-7 and NIH3T3 cells stably expressing deltagamma1 showed significantly less irradiation-induced Mdm2 phosphorylation [2].
  • We analyzed Mdm2 expression between 7.5 and 9 days post-coitum (dpc) by whole-mount in situ hybridization and report here a novel expression pattern during neural crest development [31].
  • Surprisingly, microinjection of Mdm2 mRNA in two-cell-stage embryos led to inhibition of cellular convergence during gastrulation [32].
  • Quantitative RT-PCR analysis revealed no increased mRNA levels in TCDD-treated rats, but immunohistological studies indicated that TCDD modulated Mdm2 protein levels, and in particular, increased nuclear levels in rat hepatocytes in situ [33].
  • Finally, immunofluorescence experiments showed that both p63 isoforms were localized in the nucleus and could be exported when coexpressed with Mdm2 but not with MdmX [34].


  1. Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Xiong, S., Van Pelt, C.S., Elizondo-Fraire, A.C., Liu, G., Lozano, G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance. Koma, Y.I., Ito, A., Watabe, K., Kimura, S.H., Kitamura, Y. Histol. Histopathol. (2004) [Pubmed]
  3. Immunohistochemical analysis for Mdm2 and p53 proteins in methylcholanthrene-induced mouse rhabdomyosarcomas. Wu, H., Inoue, M. J. Vet. Med. Sci. (2006) [Pubmed]
  4. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Eischen, C.M., Weber, J.D., Roussel, M.F., Sherr, C.J., Cleveland, J.L. Genes Dev. (1999) [Pubmed]
  5. Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. Uchida, C., Miwa, S., Kitagawa, K., Hattori, T., Isobe, T., Otani, S., Oda, T., Sugimura, H., Kamijo, T., Ookawa, K., Yasuda, H., Kitagawa, M. EMBO J. (2005) [Pubmed]
  6. NEDD4-1 Is a Proto-Oncogenic Ubiquitin Ligase for PTEN. Wang, X., Trotman, L.C., Koppie, T., Alimonti, A., Chen, Z., Gao, Z., Wang, J., Erdjument-Bromage, H., Tempst, P., Cordon-Cardo, C., Pandolfi, P.P., Jiang, X. Cell (2007) [Pubmed]
  7. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., McCormick, F. Cell (2000) [Pubmed]
  8. Mdm2 promotes the rapid degradation of p53. Haupt, Y., Maya, R., Kazaz, A., Oren, M. Nature (1997) [Pubmed]
  9. Regulation of p53 stability by Mdm2. Kubbutat, M.H., Jones, S.N., Vousden, K.H. Nature (1997) [Pubmed]
  10. p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. Zhu, Y., Mao, X.O., Sun, Y., Xia, Z., Greenberg, D.A. J. Biol. Chem. (2002) [Pubmed]
  11. Circumvention and reactivation of the p53 oncogene checkpoint in mouse colon tumors. Aizu, W., Belinsky, G.S., Flynn, C., Noonan, E.J., Boes, C.C., Godman, C.A., Doshi, B., Nambiar, P.R., Rosenberg, D.W., Giardina, C. Biochem. Pharmacol. (2006) [Pubmed]
  12. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Bernardi, R., Scaglioni, P.P., Bergmann, S., Horn, H.F., Vousden, K.H., Pandolfi, P.P. Nat. Cell Biol. (2004) [Pubmed]
  13. Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. Feng, J., Tamaskovic, R., Yang, Z., Brazil, D.P., Merlo, A., Hess, D., Hemmings, B.A. J. Biol. Chem. (2004) [Pubmed]
  14. Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair. Alt, J.R., Bouska, A., Fernandez, M.R., Cerny, R.L., Xiao, H., Eischen, C.M. J. Biol. Chem. (2005) [Pubmed]
  15. Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Steinman, H.A., Hoover, K.M., Keeler, M.L., Sands, A.T., Jones, S.N. Oncogene (2005) [Pubmed]
  16. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Bertwistle, D., Sugimoto, M., Sherr, C.J. Mol. Cell. Biol. (2004) [Pubmed]
  17. Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2. Wang, P., Gao, H., Ni, Y., Wang, B., Wu, Y., Ji, L., Qin, L., Ma, L., Pei, G. J. Biol. Chem. (2003) [Pubmed]
  18. Loss of p19ARF enhances the defects of Mdm2 overexpression in the mammary gland. Foster, C.J., Lozano, G. Oncogene (2002) [Pubmed]
  19. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Jones, S.N., Roe, A.E., Donehower, L.A., Bradley, A. Nature (1995) [Pubmed]
  20. Hypophosphorylation of Mdm2 augments p53 stability. Blattner, C., Hay, T., Meek, D.W., Lane, D.P. Mol. Cell. Biol. (2002) [Pubmed]
  21. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Maya, R., Balass, M., Kim, S.T., Shkedy, D., Leal, J.F., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., Kastan, M.B., Katzir, E., Oren, M. Genes Dev. (2001) [Pubmed]
  22. A role for the polyproline domain of p53 in its regulation by Mdm2. Berger, M., Vogt Sionov, R., Levine, A.J., Haupt, Y. J. Biol. Chem. (2001) [Pubmed]
  23. The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2. Jones, S.N., Sands, A.T., Hancock, A.R., Vogel, H., Donehower, L.A., Linke, S.P., Wahl, G.M., Bradley, A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  24. Nucleolar Arf sequesters Mdm2 and activates p53. Weber, J.D., Taylor, L.J., Roussel, M.F., Sherr, C.J., Bar-Sagi, D. Nat. Cell Biol. (1999) [Pubmed]
  25. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Francoz, S., Froment, P., Bogaerts, S., De Clercq, S., Maetens, M., Doumont, G., Bellefroid, E., Marine, J.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  26. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. Alt, J.R., Greiner, T.C., Cleveland, J.L., Eischen, C.M. EMBO J. (2003) [Pubmed]
  27. Abrogation of G1 arrest after DNA damage is associated with constitutive overexpression of Mdm2, Cdk4, and Irf1 mRNAs in the BALB/c 3T3 A31 variant 1-1 clone. Nozaki, T., Masutani, M., Sugimura, T., Takato, T., Wakabayashi, K. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  28. Reduced hepatic tumor incidence in cyclin G1-deficient mice. Jensen, M.R., Factor, V.M., Fantozzi, A., Helin, K., Huh, C.G., Thorgeirsson, S.S. Hepatology (2003) [Pubmed]
  29. Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Grier, J.D., Xiong, S., Elizondo-Fraire, A.C., Parant, J.M., Lozano, G. Mol. Cell. Biol. (2006) [Pubmed]
  30. Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. Lengner, C.J., Steinman, H.A., Gagnon, J., Smith, T.W., Henderson, J.E., Kream, B.E., Stein, G.S., Lian, J.B., Jones, S.N. J. Cell Biol. (2006) [Pubmed]
  31. Preferential expression of Mdm2 oncogene during the development of neural crest and its derivatives in mouse early embryogenesis. Daujat, S., Neel, H., Piette, J. Mech. Dev. (2001) [Pubmed]
  32. The Mdm2 gene of zebrafish (Danio rerio): preferential expression during development of neural and muscular tissues, and absence of tumor formation after overexpression of its cDNA during early embryogenesis. Thisse, C., Neel, H., Thisse, B., Daujat, S., Piette, J. Differentiation (2000) [Pubmed]
  33. TCDD activates Mdm2 and attenuates the p53 response to DNA damaging agents. Pääjärvi, G., Viluksela, M., Pohjanvirta, R., Stenius, U., Högberg, J. Carcinogenesis (2005) [Pubmed]
  34. Regulation of p63 function by Mdm2 and MdmX. Kadakia, M., Slader, C., Berberich, S.J. DNA Cell Biol. (2001) [Pubmed]
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