Mutual dependence of MDM2 and MDMX in their functional inactivation of p53

Jijie Gu, Hidehiko Kawai, Linghu Nie, Hiroyuki Kitao, Dmitri Wiederschain, Aart G. Jochemsen, John Parant, Guillermina Lozano, Zhi Min Yuan

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

MDMX, an MDM2-related protein, has emerged as yet another essential negative regulator of p53 tumor suppressor, since loss of MDMX expression results in p53-dependent embryonic lethality in mice. However, it remains unknown why neither homologue can compensate for the loss of the other. In addition, results of biochemical studies have suggested that MDMX inhibits MDM2-mediated p53 degradation, thus contradicting its role as defined in gene knockout experiments. Using cells deficient in either MDM2 or MDMX, we demonstrated that these two p53 inhibitors are in fact functionally dependent on each other. In the absence of MDMX, MDM2 is largely ineffective in down-regulating p53 because of its extremely short half-life. MDIMX renders MDM2 protein sufficiently stable to function at its full potential for p53 degradation. On the other hand, MDMX, which is a cytoplasmic protein, depends on MDM2 to redistribute into the nucleus and be able to inactivate p53. We also showed that MDMX, when exceedingly overexpressed, inhibits MDM2-mediated p53 degradation by competing with MDM2 for p53 binding. Our findings therefore provide a molecular basis for the nonoverlapping activities of these two p53 inhibitors previously revealed in genetic studies.

Original languageEnglish
Pages (from-to)19251-19254
Number of pages4
JournalJournal of Biological Chemistry
Volume277
Issue number22
DOIs
Publication statusPublished - May 31 2002
Externally publishedYes

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Degradation
Gene Knockout Techniques
Proteins
Half-Life
Tumors
Genes
Neoplasms
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gu, J., Kawai, H., Nie, L., Kitao, H., Wiederschain, D., Jochemsen, A. G., ... Yuan, Z. M. (2002). Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. Journal of Biological Chemistry, 277(22), 19251-19254. https://doi.org/10.1074/jbc.C200150200

Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. / Gu, Jijie; Kawai, Hidehiko; Nie, Linghu; Kitao, Hiroyuki; Wiederschain, Dmitri; Jochemsen, Aart G.; Parant, John; Lozano, Guillermina; Yuan, Zhi Min.

In: Journal of Biological Chemistry, Vol. 277, No. 22, 31.05.2002, p. 19251-19254.

Research output: Contribution to journalArticle

Gu, J, Kawai, H, Nie, L, Kitao, H, Wiederschain, D, Jochemsen, AG, Parant, J, Lozano, G & Yuan, ZM 2002, 'Mutual dependence of MDM2 and MDMX in their functional inactivation of p53', Journal of Biological Chemistry, vol. 277, no. 22, pp. 19251-19254. https://doi.org/10.1074/jbc.C200150200
Gu, Jijie ; Kawai, Hidehiko ; Nie, Linghu ; Kitao, Hiroyuki ; Wiederschain, Dmitri ; Jochemsen, Aart G. ; Parant, John ; Lozano, Guillermina ; Yuan, Zhi Min. / Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 22. pp. 19251-19254.
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