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Gene Review

MDM4  -  MDM4, p53 regulator

Homo sapiens

Synonyms: Double minute 4 protein, HDMX, MDMX, MRP1, Mdm2-like p53-binding protein, ...
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Disease relevance of MDM4


High impact information on MDM4

  • Thus, MDM2 and MDM4 are nonoverlapping critical regulators of p53 in vivo [6].
  • 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation [7].
  • Interestingly, in response to UV irradiation, the wild-type, but not the kinase-dead mutant, Chk1 phosphorylated MDMX at serine 367, enhanced the 14-3-3gamma-MDMX binding and the cytoplasmic retaining of MDMX [7].
  • DNA damage promotes MDMX phosphorylation, nuclear translocation, and degradation by MDM2 [8].
  • The MDM2 homolog MDMX is an important regulator of p53 during mouse embryonic development [8].

Biological context of MDM4


Anatomical context of MDM4

  • MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts [13].
  • The human MDMX gene is transcribed in all tissues tested, with high levels in thymus [10].
  • To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs) [14].
  • When this SNP was recapitulated in an in vitro MRP1 promoter-reporter assay, significantly lower activity was observed from the G-containing promoter when compared with the C-containing promoter in all four cell lines that we tested (P<0.01) [15].
  • These results indicate that MRP-1/CD9 regulates the actin cytoskeleton by downregulating of the WAVE2, through the Wnt-independent signal pathway.Oncogene (2006) 25, 6480-6488. doi:10.1038/sj.onc.1209654; published online 8 May 2006 [16].

Associations of MDM4 with chemical compounds

  • Similarly, activation of endogenous p53 by adriamycin enhances MDMX cleavage and produces a marked decrease of its intracellular levels, while not affecting the D361A-MDMX mutant [13].
  • We found that double mutation of two lysine residues, K254 and K379, abrogated MDMX sumoylation in vivo [17].
  • MDMX overexpression does not accelerate tumor growth but increases resistance to 5-FU treatment in vivo [18].
  • Knockdown of MDMX increases sensitivity to actinomycin D, whereas MDMX overexpression abrogates p53 activation and prevents growth arrest [18].
  • Although this proteolytic degradation can be blocked by the protease inhibitors bafilomycin A(1), N-acetyl-Leu-Leu-Norleu-AL, and N-acetyl-Leu-Leu-Met-AL, MDMX degradation is not inhibited by lactacystin, suggesting that degradation occurs by a proteasome-independent mechanism [19].

Physical interactions of MDM4

  • Phosphorylated MDMX is selectively bound and degraded by MDM2 preceding p53 accumulation and activation [11].
  • MDM2 and MDMX bind and stabilize the p53-related protein p73 [20].
  • These results suggest that CK1alpha is a functionally relevant MDMX-binding protein and plays an important role in regulating p53 activity in the absence or presence of stress [21].

Regulatory relationships of MDM4

  • MDMX level is regulated by MDM2-mediated poly-ubiquitination, which results in its accelerated degradation after DNA damage or expression of ARF [17].
  • The E2F-1 transcription factor is negatively regulated by its interaction with the MDMX protein [22].
  • Chk2 also stimulates MDMX ubiquitination and degradation by MDM2 [11].
  • MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins [23].
  • The DNA damage inducibility of these p53 responsive promoters was suppressed better by MDMX-S than by MDMX [24].
  • Our data suggest that stabilization of MDMX by Akt may be an alternative mechanism by which Akt up-regulates MDM2 protein levels and exerts its oncogenic effects on p53 in tumor cells [25].

Other interactions of MDM4


Analytical, diagnostic and therapeutic context of MDM4


  1. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Riemenschneider, M.J., Büschges, R., Wolter, M., Reifenberger, J., Boström, J., Kraus, J.A., Schlegel, U., Reifenberger, G. Cancer Res. (1999) [Pubmed]
  2. Significance of HDMX-S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis. Bartel, F., Schulz, J., Böhnke, A., Blümke, K., Kappler, M., Bache, M., Schmidt, H., Würl, P., Taubert, H., Hauptmann, S. Int. J. Cancer (2005) [Pubmed]
  3. Real-time quantitative PCR analysis of regions involved in gene amplification reveals gene overdose in low-grade astrocytic gliomas. Arjona, D., Bello, M.J., Alonso, M.E., Isla, A., De Campos, J.M., Vaquero, J., Sarasa, J.L., Gutierrez, M., Rey, J.A. Diagn. Mol. Pathol. (2005) [Pubmed]
  4. MDMX: from bench to bedside. Marine, J.C., Dyer, M.A., Jochemsen, A.G. J. Cell. Sci. (2007) [Pubmed]
  5. An Organometallic Protein Kinase Inhibitor Pharmacologically Activates p53 and Induces Apoptosis in Human Melanoma Cells. Smalley, K.S., Contractor, R., Haass, N.K., Kulp, A.N., Atilla-Gokcumen, G.E., Williams, D.S., Bregman, H., Flaherty, K.T., Soengas, M.S., Meggers, E., Herlyn, M. Cancer Res. (2007) [Pubmed]
  6. 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]
  7. 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. Jin, Y., Dai, M.S., Lu, S.Z., Xu, Y., Luo, Z., Zhao, Y., Lu, H. EMBO J. (2006) [Pubmed]
  8. Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. LeBron, C., Chen, L., Gilkes, D.M., Chen, J. EMBO J. (2006) [Pubmed]
  9. MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis. Mancini, F., Gentiletti, F., D'Angelo, M., Giglio, S., Nanni, S., D'Angelo, C., Farsetti, A., Citro, G., Sacchi, A., Pontecorvi, A., Moretti, F. J. Biol. Chem. (2004) [Pubmed]
  10. Isolation and identification of the human homolog of a new p53-binding protein, Mdmx. Shvarts, A., Bazuine, M., Dekker, P., Ramos, Y.F., Steegenga, W.T., Merckx, G., van Ham, R.C., van der Houven van Oordt, W., van der Eb, A.J., Jochemsen, A.G. Genomics (1997) [Pubmed]
  11. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. Chen, L., Gilkes, D.M., Pan, Y., Lane, W.S., Chen, J. EMBO J. (2005) [Pubmed]
  12. MDMX: a novel p53-binding protein with some functional properties of MDM2. Shvarts, A., Steegenga, W.T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R.C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A.J., Jochemsen, A.G. EMBO J. (1996) [Pubmed]
  13. MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts. Gentiletti, F., Mancini, F., D'Angelo, M., Sacchi, A., Pontecorvi, A., Jochemsen, A.G., Moretti, F. Oncogene (2002) [Pubmed]
  14. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death. Boesten, L.S., Zadelaar, S.M., De Clercq, S., Francoz, S., van Nieuwkoop, A., Biessen, E.A., Hofmann, F., Feil, S., Feil, R., Jochemsen, A.G., Zurcher, C., Havekes, L.M., van Vlijmen, B.J., Marine, J.C. Cell Death Differ. (2006) [Pubmed]
  15. A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection. Wang, Z., Wang, B., Tang, K., Lee, E.J., Chong, S.S., Lee, C.G. Hum. Mol. Genet. (2005) [Pubmed]
  16. MRP-1/CD9 gene transduction regulates the actin cytoskeleton through the downregulation of WAVE2. Huang, C.L., Ueno, M., Liu, D., Masuya, D., Nakano, J., Yokomise, H., Nakagawa, T., Miyake, M. Oncogene (2006) [Pubmed]
  17. Modification of MDMX by sumoylation. Pan, Y., Chen, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  18. MDMX regulation of p53 response to ribosomal stress. Gilkes, D.M., Chen, L., Chen, J. EMBO J. (2006) [Pubmed]
  19. A transcriptionally inactive E2F-1 targets the MDM family of proteins for proteolytic degradation. Strachan, G.D., Rallapalli, R., Pucci, B., Lafond, T.P., Hall, D.J. J. Biol. Chem. (2001) [Pubmed]
  20. MDM2 and MDMX bind and stabilize the p53-related protein p73. Ongkeko, W.M., Wang, X.Q., Siu, W.Y., Lau, A.W., Yamashita, K., Harris, A.L., Cox, L.S., Poon, R.Y. Curr. Biol. (1999) [Pubmed]
  21. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Chen, L., Li, C., Pan, Y., Chen, J. Mol. Cell. Biol. (2005) [Pubmed]
  22. The E2F-1 transcription factor is negatively regulated by its interaction with the MDMX protein. Strachan, G.D., Jordan-Sciutto, K.L., Rallapalli, R., Tuan, R.S., Hall, D.J. J. Cell. Biochem. (2003) [Pubmed]
  23. 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]
  24. Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells. Rallapalli, R., Strachan, G., Tuan, R.S., Hall, D.J. J. Cell. Biochem. (2003) [Pubmed]
  25. Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding. Lopez-Pajares, V., Kim, M.M., Yuan, Z.M. J. Biol. Chem. (2008) [Pubmed]
  26. Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target. Riemenschneider, M.J., Knobbe, C.B., Reifenberger, G. Int. J. Cancer (2003) [Pubmed]
  27. Loss of Kv and MaxiK currents associated with increased MRP1 expression in small cell lung carcinoma. Lam, H.D., Lemay, A.M., Kelly, J., Hill, C.E. J. Cell. Physiol. (2006) [Pubmed]
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