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Mdm4  -  transformed mouse 3T3 cell double minute 4

Mus musculus

Synonyms: 4933417N07Rik, AA414968, AL023055, AU018793, AU021806, ...
 
 
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Disease relevance of Mdm4

  • Mice lacking Mdm2 in the CNS developed hydranencephaly at embryonic day 12.5 due to apoptosis, whereas Mdm4 deletion showed a proencephaly phenotype at embryonic day 17.5 because of cell cycle arrest and apoptosis [1].
  • Furthermore, the human Mdmx ortholog, Hdmx, was found to be overexpressed in a significant percentage of various human tumors and amplified in 5% of primary breast tumors, all of which retained wild-type p53 [2].
 

High impact information on Mdm4

  • Mdm4-null mice died at 7.5-8.5 dpc, owing to loss of cell proliferation and not induction of apoptosis [3].
  • Thus, these in vivo data demonstrate the importance of Mdm4 independent of Mdm2 in inhibition of p53 [1].
  • We deleted Mdm2 and Mdm4 in cardiomyocytes, since proliferation and apoptosis are important processes in heart development [4].
  • Here we show that retrovirus-mediated Mdmx overexpression allows primary mouse embryonic fibroblast immortalization and leads to neoplastic transformation in combination with HRas(V12) [2].
  • Moreover, extensive p53-dependent cell death was specifically detected in the developing central nervous system of the Mdm4 mutant embryos [5].
 

Biological context of Mdm4

  • Finally, we provide evidence indicating that Mdm4 plays no role on cell proliferation or cell cycle control that is distinct from its ability to modulate p53 function [5].
  • Surprisingly, the absence of p21 also uncovers an antiproliferative effect of Mdm4 on cell growth in vitro and in Mdm4-heterozygous mice [6].
  • 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].
  • 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 [7].
  • Mdm4 loss did not alter Mdm2 stability but significantly increased p53DeltaP transactivation to partially restore cycle control [8].
 

Anatomical context of Mdm4

  • Accordingly, Mdm4-deficient mouse embryonic fibroblasts manifested a greatly reduced proliferative capacity in culture [5].
 

Regulatory relationships of Mdm4

  • Like Mdm2, the absence of Mdm4 has recently been found to induce embryonic lethality in mice that is rescued by p53 deletion [6].
 

Other interactions of Mdm4

 

Analytical, diagnostic and therapeutic context of Mdm4

  • Furthermore, Mdm4 loss dramatically improved p53DeltaP-mediated suppression of oncogene-induced tumors, emphasizing the importance of targeting Mdm4 in chemotherapies designed to activate p53 [8].
  • We can show by co-immunoprecipitation that the MDMX protein interacts specifically with p53 in vivo [10].

References

  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. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Danovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., de Graaf, P., Francoz, S., Gasparini, P., Gobbi, A., Helin, K., Pelicci, P.G., Jochemsen, A.G., Marine, J.C. Mol. Cell. Biol. (2004) [Pubmed]
  3. 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]
  4. 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]
  5. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Migliorini, D., Lazzerini Denchi, E., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., Helin, K., Pelicci, P.G., Marine, J.C. Mol. Cell. Biol. (2002) [Pubmed]
  6. Absence of p21 partially rescues Mdm4 loss and uncovers an antiproliferative effect of Mdm4 on cell growth. Steinman, H.A., Sluss, H.K., Sands, A.T., Pihan, G., Jones, S.N. Oncogene (2004) [Pubmed]
  7. 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]
  8. A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network. Toledo, F., Krummel, K.A., Lee, C.J., Liu, C.W., Rodewald, L.W., Tang, M., Wahl, G.M. Cancer Cell (2006) [Pubmed]
  9. Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice. Iwakuma, T., Parant, J.M., Fasulo, M., Zwart, E., Jacks, T., de Vries, A., Lozano, G. Oncogene (2004) [Pubmed]
  10. 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]
 
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