Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
| Autor: | Toshiyuki Obata, Yuko Isazawa, Keiji Tanaka, Toshiaki Suzuki, Yoko Ogawara, Shohei Kishishita, Yukiko Gotoh, Norihisa Masuyama |
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| Rok vydání: | 2002 |
| Předmět: |
Time Factors
Cell Survival Morpholines Blotting Western Retroviridae Proteins Oncogenic Apoptosis Protein Serine-Threonine Kinases Biochemistry Phosphatidylinositol 3-Kinases chemistry.chemical_compound Ubiquitin Proto-Oncogene Proteins Serine Tumor Cells Cultured Humans LY294002 RNA Messenger Phosphatidylinositol Enzyme Inhibitors Phosphorylation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Dose-Response Relationship Drug biology Reverse Transcriptase Polymerase Chain Reaction Chemistry Nuclear Proteins Proto-Oncogene Proteins c-mdm2 Cell Biology Precipitin Tests Recombinant Proteins Ubiquitin ligase Cell biology Oncogene Protein v-akt enzymes and coenzymes (carbohydrates) Microscopy Fluorescence Chromones biology.protein Cancer research Mdm2 Tumor Suppressor Protein p53 Proto-Oncogene Proteins c-akt Plasmids Protein Binding Subcellular Fractions |
| Zdroj: | Journal of Biological Chemistry. 277:21843-21850 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109745200 |
| Popis: | p53 plays a key role in DNA damage-induced apoptosis. Recent studies have reported that the phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis, although the underlying mechanisms have yet to be determined. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. In this study, we find that expression of Akt reduces the protein levels of p53, at least in part by enhancing the degradation of p53. Both Akt expression and serum treatment induced phosphorylation of Mdm2 at Ser186. Akt-mediated phosphorylation of Mdm2 at Ser186 had little effect on the subcellular localization of Mdm2. However, both Akt expression and serum treatment increased Mdm2 ubiquitination of p53. The serum-induced increase in p53 ubiquitination was blocked by LY294002, a phosphatidylinositol 3-OH-kinase inhibitor. Moreover, when Ser186 was replaced by Ala, Mdm2 became resistant to Akt enhancement of p53 ubiquitination and degradation. Collectively, these results suggest that Akt enhances the ubiquitination-promoting function of Mdm2 by phosphorylation of Ser186, which results in reduction of p53 protein. This study may shed light on the mechanisms by which Akt promotes survival, proliferation, and tumorigenesis. |
| Databáze: | OpenAIRE |
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