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Mdm2 promotes the rapid degradation of p53

Nature volume 387, pages 296–299 (1997)Cite this article

Abstract

The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress1. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins1,2. The Mdm2 oncoprotein is a potent inhibitor of p53 (ref. 3). Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes3,4 and to exert antiproliferative effects4–7. On the other hand, p53 activates the expression of the mdm2 gene1 in an autoregulatory feedback loop3. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects8. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

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Authors and Affiliations

  1. Lautenberg Center for General and Tumor Immunology, The Hebrew University Haddassah Medical School, Jerusalem, 91120, Israel

    Ygal Haupt

  2. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Ruth Maya, Anat Kazaz & Moshe Oren

Authors
  1. Ygal Haupt
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  2. Ruth Maya
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  3. Anat Kazaz
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  4. Moshe Oren
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Haupt, Y., Maya, R., Kazaz, A. et al. Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997). https://doi.org/10.1038/387296a0

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