Downregulation of MDM2 stabilizes p53 by inhibiting p53 ubiquitination in response to specific alkylating agents.
p53 is stabilized in response to DNA damaging stress. This stabilization is thought to result from phosphorylation in the N-terminus of p53, which inhibits p53:MDM2 binding, and prevents MDM2 from promoting p53 ubiquitination. In this report, the DNA alkylating agents mitomycin C (MMC) and methylmethane sulfonate (MMS), as well as UV radiation, stabilized p53 in a manner independent of phosphorylation in p53 N-terminus. This stabilization coincided with decreased levels of MDM2 mRNA and protein, and a corresponding decrease in p53 ubiquitination. Importantly, MDM2 overexpression inhibited the stabilization of p53 and decrease in ubiquitination following MMC, MMS, and UV treatment. This indicates that downregulation of MDM2 contributes to the stabilization of p53 in response to these agents.
Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115, USA.
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Inoue
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Geyer
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Yu
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Maki
D000477:Alkylating Agents / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation; D009687:Nuclear Proteins; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014466:Ultraviolet Rays
D000477:Alkylating Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D010768:Phosphoserine; D016685:Mitomycin; D008741:Methyl Methanesulfonate; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2