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Gene Review

MDM2  -  MDM2 proto-oncogene, E3 ubiquitin protein...

Homo sapiens

Synonyms: ACTFS, Double minute 2 protein, E3 ubiquitin-protein ligase Mdm2, HDM2, HDMX, ...
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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 [10].
  • These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers [11].
  • p53 is regulated by multiple posttranslational modifications, including Hdm2-mediated ubiquitylation that drives its proteasomal degradation [12].
  • Induction of hnRNP K ensues through the inhibition of its ubiquitin-dependent proteasomal degradation mediated by the ubiquitin E3 ligase HDM2/MDM2 [13].
  • A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans [14].

Chemical compound and disease context of MDM2


Biological context of MDM2

  • DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2 [20].
  • Unlike MDM2, however, MDM4 does not cause nuclear export or degradation of p53 (refs. 9,10) [21].
  • In this regard, the p300 C/H1 region serves as a specific in vivo binding site for both p53 and MDM2, a naturally occurring p53 destabilizer [22].
  • Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification [23].
  • CONCLUSIONS: The present data provide further indications that increased MDM2 expression level, caused by gene amplification or altered regulation of transcription, is involved in tumor progression of some, but not all, sarcoma subtypes [2].

Anatomical context of MDM2


Associations of MDM2 with chemical compounds


Physical interactions of MDM2

  • We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2 [31].
  • By fusing portions of MDM2 to a heterologous DNA-binding domain to allow p53-independent promoter recruitment, we have localized this inhibitory domain to a region encompassing amino acids 50-222 of MDM2 [32].
  • Using a yeast two-hybrid screen, we have identified a gene that encodes a novel cellular protein (MTBP) that binds to MDM2 [33].
  • Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm [34].
  • Here we report that MDM2 physically interacts with a structurally related protein termed MDMX [35].
  • Herein, we demonstrate that S7 binds to MDM2, in vitro and in vivo, and that the interaction between MDM2 and S7 leads to modulation of MDM2-p53 binding by forming a ternary complex among MDM2, p53 and S7 [36].

Enzymatic interactions of MDM2


Co-localisations of MDM2

  • Interestingly, the MDM2 protein was found to co-localize with p53 to nucleolar structures following proteasome inhibition [41].

Regulatory relationships of MDM2

  • It has therefore been suggested that MDM2 acts to inhibit p53 by concealing its activation domain from the basal machinery [32].
  • Furthermore, loss of PTEN can result in resistance to apoptosis by activating MDM2-mediated antiapoptotic mechanism [15].
  • Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit [42].
  • These results demonstrate that MDM2 regulates the stability of PCAF by ubiquitinating and degrading this protein [26].
  • The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition [43].
  • Mechanistically, TAFII250 downregulates Mdm2 auto-ubiquitylation, leading to Mdm2 stabilization, and promotes p53-Mdm2 association through a recently defined second binding site in the acidic domain of Mdm2 [44].

Other interactions of MDM2

  • This interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2 [31].
  • Repression of p53-mediated transcription by MDM2: a dual mechanism [32].
  • Here we show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1 [45].
  • Southern blot analysis of this tumor revealed amplification of CDK4 and MDM2 [46].
  • Here we report that TSG101 participates with MDM2 in an autoregulatory loop that modulates the cellular levels of both proteins, and also of p53, by affecting protein decay [47].
  • This is the first demonstration that MDM2 possesses an intrinsic molecular chaperone activity, indicating that the ATP binding function of MDM2 can mediate its chaperone function toward the p53 tumor suppressor [48].

Analytical, diagnostic and therapeutic context of MDM2

  • To determine the MDM2 and TP53 mRNA levels, Northern-blot analysis was performed [2].
  • The anti-MDM2 oligonucleotide showed antitumor activity and increased therapeutic effectiveness of paclitaxel in both LNCaP and PC3 xenografts, causing changes in gene expression similar to those seen in vitro [3].
  • We show here that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner [37].
  • Immunofluorescence staining indicated that ectopically expressed SMAD4 was present in both the cytoplasm and nucleus, and MDM2 and NIDMX were localized mainly to the nucleus and cytoplasm, respectively [49].
  • Inhibition appears to result from titration of general transcription factors because MDM2 overexpression inhibits c-fos as well as other promoters in vivo and basal transcription in vitro [50].


  1. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Xiao, Z.X., Chen, J., Levine, A.J., Modjtahedi, N., Xing, J., Sellers, W.R., Livingston, D.M. Nature (1995) [Pubmed]
  2. MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. Flørenes, V.A., Maelandsmo, G.M., Forus, A., Andreassen, A., Myklebost, O., Fodstad, O. J. Natl. Cancer Inst. (1994) [Pubmed]
  3. Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Zhang, Z., Li, M., Wang, H., Agrawal, S., Zhang, R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. The tumor suppressor p53 and the oncoprotein simian virus 40 T antigen bind to overlapping domains on the MDM2 protein. Brown, D.R., Deb, S., Muñoz, R.M., Subler, M.A., Deb, S.P. Mol. Cell. Biol. (1993) [Pubmed]
  5. MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells. Teoh, G., Urashima, M., Ogata, A., Chauhan, D., DeCaprio, J.A., Treon, S.P., Schlossman, R.L., Anderson, K.C. Blood (1997) [Pubmed]
  6. MDM2 promoter SNP309 is associated with risk of occurrence and advanced lymph node metastasis of nasopharyngeal carcinoma in Chinese population. Zhou, G., Zhai, Y., Cui, Y., Zhang, X., Dong, X., Yang, H., He, Y., Yao, K., Zhang, H., Zhi, L., Yuan, X., Qiu, W., Zhang, X., Shen, Y., Qiang, B., He, F. Clin. Cancer Res. (2007) [Pubmed]
  7. MDM2 SNP309 polymorphism as risk factor for susceptibility and poor prognosis in renal cell carcinoma. Hirata, H., Hinoda, Y., Kikuno, N., Kawamoto, K., Suehiro, Y., Tanaka, Y., Dahiya, R. Clin. Cancer Res. (2007) [Pubmed]
  8. MDM2 promoter polymorphism and pancreatic cancer risk and prognosis. Asomaning, K., Reid, A.E., Zhou, W., Heist, R.S., Zhai, R., Su, L., Kwak, E.L., Blaszkowsky, L., Zhu, A.X., Ryan, D.P., Christiani, D.C., Liu, G. Clin. Cancer Res. (2008) [Pubmed]
  9. A novel functional polymorphism C1797G in the MDM2 promoter is associated with risk of bladder cancer in a Chinese population. Wang, M., Zhang, Z., Zhu, H., Fu, G., Wang, S., Wu, D., Zhou, J., Wei, Q., Zhang, Z. Clin. Cancer Res. (2008) [Pubmed]
  10. 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]
  11. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Narita, M., Narita, M., Krizhanovsky, V., Nuñez, S., Chicas, A., Hearn, S.A., Myers, M.P., Lowe, S.W. Cell (2006) [Pubmed]
  12. E4F1 Is an Atypical Ubiquitin Ligase that Modulates p53 Effector Functions Independently of Degradation. Le Cam, L., Linares, L.K., Paul, C., Julien, E., Lacroix, M., Hatchi, E., Triboulet, R., Bossis, G., Shmueli, A., Rodriguez, M.S., Coux, O., Sardet, C. Cell (2006) [Pubmed]
  13. hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Moumen, A., Masterson, P., O'Connor, M.J., Jackson, S.P. Cell (2005) [Pubmed]
  14. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Bond, G.L., Hu, W., Bond, E.E., Robins, H., Lutzker, S.G., Arva, N.C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., Onel, K., Yip, L., Hwang, S.J., Strong, L.C., Lozano, G., Levine, A.J. Cell (2004) [Pubmed]
  15. PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Zhou, M., Gu, L., Findley, H.W., Jiang, R., Woods, W.G. Cancer Res. (2003) [Pubmed]
  16. Combined targeting of epidermal growth factor receptor and MDM2 by gefitinib and antisense MDM2 cooperatively inhibit hormone-independent prostate cancer. Bianco, R., Caputo, R., Caputo, R., Damiano, V., De Placido, S., Ficorella, C., Agrawal, S., Bianco, A.R., Ciardiello, F., Tortora, G. Clin. Cancer Res. (2004) [Pubmed]
  17. MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells. Saji, S., Okumura, N., Eguchi, H., Nakashima, S., Suzuki, A., Toi, M., Nozawa, Y., Saji, S., Hayashi , S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  18. Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. Alonso, M., Tamasdan, C., Miller, D.C., Newcomb, E.W. Mol. Cancer Ther. (2003) [Pubmed]
  19. Genistein, a dietary isoflavone, down-regulates the MDM2 oncogene at both transcriptional and posttranslational levels. Li, M., Zhang, Z., Hill, D.L., Chen, X., Wang, H., Zhang, R. Cancer Res. (2005) [Pubmed]
  20. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Shieh, S.Y., Ikeda, M., Taya, Y., Prives, C. Cell (1997) [Pubmed]
  21. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Parant, J., Chavez-Reyes, A., Little, N.A., Yan, W., Reinke, V., Jochemsen, A.G., Lozano, G. Nat. Genet. (2001) [Pubmed]
  22. p300/MDM2 complexes participate in MDM2-mediated p53 degradation. Grossman, S.R., Perez, M., Kung, A.L., Joseph, M., Mansur, C., Xiao, Z.X., Kumar, S., Howley, P.M., Livingston, D.M. Mol. Cell (1998) [Pubmed]
  23. Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification. Habuchi, T., Kinoshita, H., Yamada, H., Kakehi, Y., Ogawa, O., Wu, W.J., Takahashi, R., Sugiyama, T., Yoshida, O. J. Natl. Cancer Inst. (1994) [Pubmed]
  24. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Dai, M.S., Zeng, S.X., Jin, Y., Sun, X.X., David, L., Lu, H. Mol. Cell. Biol. (2004) [Pubmed]
  25. Cul4A physically associates with MDM2 and participates in the proteolysis of p53. Nag, A., Bagchi, S., Raychaudhuri, P. Cancer Res. (2004) [Pubmed]
  26. MDM2 mediates p300/CREB-binding protein-associated factor ubiquitination and degradation. Jin, Y., Zeng, S.X., Lee, H., Lu, H. J. Biol. Chem. (2004) [Pubmed]
  27. p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells. Takemoto, S., Trovato, R., Cereseto, A., Nicot, C., Kislyakova, T., Casareto, L., Waldmann, T., Torelli, G., Franchini, G. Blood (2000) [Pubmed]
  28. The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma. Sheikh, M.S., Shao, Z.M., Hussain, A., Fontana, J.A. Cancer Res. (1993) [Pubmed]
  29. The epithelial cell transforming sequence 2, a guanine nucleotide exchange factor for Rho GTPases, is repressed by p53 via protein methyltransferases and is required for G1-S transition. Scoumanne, A., Chen, X. Cancer Res. (2006) [Pubmed]
  30. p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Esteller, M., Cordon-Cardo, C., Corn, P.G., Meltzer, S.J., Pohar, K.S., Watkins, D.N., Capella, G., Peinado, M.A., Matias-Guiu, X., Prat, J., Baylin, S.B., Herman, J.G. Cancer Res. (2001) [Pubmed]
  31. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Zhang, Y., Xiong, Y., Yarbrough, W.G. Cell (1998) [Pubmed]
  32. Repression of p53-mediated transcription by MDM2: a dual mechanism. Thut, C.J., Goodrich, J.A., Tjian, R. Genes Dev. (1997) [Pubmed]
  33. A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2. Boyd, M.T., Vlatkovic, N., Haines, D.S. J. Biol. Chem. (2000) [Pubmed]
  34. Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. Sengupta, S., Wasylyk, B. Genes Dev. (2001) [Pubmed]
  35. Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. Sharp, D.A., Kratowicz, S.A., Sank, M.J., George, D.L. J. Biol. Chem. (1999) [Pubmed]
  36. Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function. Chen, D., Zhang, Z., Li, M., Wang, W., Li, Y., Rayburn, E.R., Hill, D.L., Wang, H., Zhang, R. Oncogene (2007) [Pubmed]
  37. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Khosravi, R., Maya, R., Gottlieb, T., Oren, M., Shiloh, Y., Shkedy, D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  38. Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2. Maki, C.G. J. Biol. Chem. (1999) [Pubmed]
  39. A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells. Pochampally, R., Fodera, B., Chen, L., Shao, W., Levine, E.A., Chen, J. Oncogene (1998) [Pubmed]
  40. Neddylating the guardian; Mdm2 catalyzed conjugation of Nedd8 to p53. Harper, J.W. Cell (2004) [Pubmed]
  41. Accumulation of soluble and nucleolar-associated p53 proteins following cellular stress. Klibanov, S.A., O'Hagan, H.M., Ljungman, M. J. Cell. Sci. (2001) [Pubmed]
  42. MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. Zhang, Z., Wang, H., Li, M., Agrawal, S., Chen, X., Zhang, R. J. Biol. Chem. (2004) [Pubmed]
  43. Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization. Rizos, H., Darmanian, A.P., Mann, G.J., Kefford, R.F. Oncogene (2000) [Pubmed]
  44. Transcription factor TAFII250 promotes Mdm2-dependent turnover of p53. Allende-Vega, N., Saville, M.K., Meek, D.W. Oncogene (2007) [Pubmed]
  45. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. Ito, A., Kawaguchi, Y., Lai, C.H., Kovacs, J.J., Higashimoto, Y., Appella, E., Yao, T.P. EMBO J. (2002) [Pubmed]
  46. Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Weber, R.G., Boström, J., Wolter, M., Baudis, M., Collins, V.P., Reifenberger, G., Lichter, P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  47. A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. Li, L., Liao, J., Ruland, J., Mak, T.W., Cohen, S.N. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  48. MDM2 chaperones the p53 tumor suppressor. Wawrzynow, B., Zylicz, A., Wallace, M., Hupp, T., Zylicz, M. J. Biol. Chem. (2007) [Pubmed]
  49. MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins. Yam, C.H., Siu, W.Y., Arooz, T., Chiu, C.H., Lau, A., Wang, X.Q., Poon, R.Y. Cancer Res. (1999) [Pubmed]
  50. The MDM2 C-terminal region binds to TAFII250 and is required for MDM2 regulation of the cyclin A promoter. Léveillard, T., Wasylyk, B. J. Biol. Chem. (1997) [Pubmed]
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