HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function
| Autor: | M S Irwin, Loretta Lau, J K Nugent, X Zhao |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Cancer Research Programmed cell death Tumor suppressor gene Transcription Genetic Immunoblotting Apoptosis Bone Neoplasms Piperazines chemistry.chemical_compound Downregulation and upregulation Puma Proto-Oncogene Proteins Genetics Humans Immunoprecipitation RNA Small Interfering skin and connective tissue diseases neoplasms Molecular Biology Gene knockdown Osteosarcoma biology Cell growth Tumor Suppressor Proteins Imidazoles Nuclear Proteins Proto-Oncogene Proteins c-mdm2 Nutlin biology.organism_classification HCT116 Cells DNA-Binding Proteins chemistry Proto-Oncogene Proteins c-bcl-2 Protein Biosynthesis Cancer research Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins Protein Binding |
| Zdroj: | Oncogene. 27(7) |
| ISSN: | 1476-5594 |
| Popis: | Nutlin-3, a small molecule inhibitor, activates p53 by disrupting p53-HDM2 association. In this study, we found that Nutlin-3 suppressed cell growth and induced apoptosis in the absence of wild-type p53, suggesting a p53-independent mechanism for Nutlin-3-induced cell death. Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. We demonstrate that Nutlin-3 inhibits endogenous binding between the proapoptotic p73 isoform TAp73alpha and HDM2 in p53-null cells. Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. p73 knockdown by siRNA results in rescue of Nutlin-3-treated cells, indicating that Nutlin-3-induced apoptosis is, at least in part, p73 dependent. In addition, Nutlin-3 treatment increases TAp73alpha protein levels with prolongation of p73 half-life. These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated. |
| Databáze: | OpenAIRE |
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