The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation Journal Article
| Authors: | Louria-Hayon, I.; Grossman, T.; Sionov, R. V.; Alsheich, O.; Pandolfi, P. P.; Haupt, Y. |
| Article Title: | The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation |
| Abstract: | The p53 protein is kept labile under normal conditions. This regulation is governed largely by its major negative regulator, Mdm2. In response to stress however, p53 accumulates and becomes activated. For this to occur, the inhibitory effects of Mdm2 have to be neutralized. Here we investigated the role of the promyelocytic leukemia protein (PML) in the activation of p53 in response to stress. We found that PML is critical for the accumulation of p53 in response to DNA damage under physiological conditions. PML protects p53 from Mdm2-mediated ubiquitination and degradation, and from inhibition of apoptosis. PML neutralizes the inhibitory effects of Mdm2 by prolonging the stress-induced phosphorylation of p53 on serine 20, a site of the checkpoint kinase 2 (Chk2). PML recruits Chk2 and p53 into the PML nuclear bodies and enhances p53/Chk2 interaction. Our results provide a novel mechanistic explanation for the cooperation between PML and p53 in response to DNA damage. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; human cell; proto-oncogene proteins; nonhuman; ubiquitin; protein function; proteins; animal cell; mouse; animals; mice; mice, knockout; dna damage; apoptosis; enzyme inhibition; protein kinases; serine; protein degradation; protein protein interaction; neoplasm proteins; cell protein; cell line; protein binding; tumor cells, cultured; transfection; phosphorylation; protein p53; time factors; animalia; transcription factors; nuclear proteins; blotting, western; dna; regulatory mechanism; ubiquitination; protein-serine-threonine kinases; tumor suppressor proteins; protein transport; promyelocytic leukemia; protein induction; tumor suppressor protein p53; active transport, cell nucleus; plasmids; stress; microscopy, fluorescence; checkpoint kinase 2; phosphotransferase; chemical reaction; bioaccumulation; protein mdm2; proto-oncogene proteins c-mdm2; protein modification; regulator protein; promyelocytic leukemia protein; degradation; protection; cell nucleus inclusion body; precipitin tests; stress analysis; humans; human; priority journal; article |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 278 |
| Issue: | 35 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2003-08-29 |
| Start Page: | 33134 |
| End Page: | 33141 |
| Language: | English |
| DOI: | 10.1074/jbc.M301264200 |
| PUBMED: | 12810724 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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