MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation
| Autor: | Girolama La Mantia, Ygal Haupt, Luisa Guerrini, Eitan Shaulian, Shira Anzi, Teresa Lopardo, Francesco Galli, Viola Calabrò, Mariangela Rossi, Osnat Alsheich-Bartok, Marco De Simone, Yuri D'Alessandra |
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| Přispěvatelé: | Galli, F, Rossi, M, D'Alessandra, Y, De Simone, M, Lopardo, T, Haupt, Y, Alsheich Bartok, O, Anzi, S, Shaulian, E, Calabro', Viola, LA MANTIA, Girolama, Guerrini, L. |
| Rok vydání: | 2010 |
| Předmět: |
Transcriptional Activation
F-Box-WD Repeat-Containing Protein 7 cell differentiation Ultraviolet Rays DNA damage Ubiquitin-Protein Ligases Cellular differentiation Active Transport Cell Nucleus Cell Cycle Proteins Biology Protein degradation Mice Cell Line Tumor Animals Humans RNA Small Interfering Kinase activity Nuclear export signal Transcription factor Cell Proliferation Cell Nucleus chemistry.chemical_classification p63 DNA ligase F-Box Proteins Tumor Suppressor Proteins Cell Differentiation Proto-Oncogene Proteins c-mdm2 Cell Biology Protein Structure Tertiary Cell biology chemistry Doxorubicin Cytoplasm Mutation protein degradation Trans-Activators Tumor Suppressor Protein p53 DNA Damage Protein Binding Transcription Factors |
| Zdroj: | Journal of Cell Science. 123:2423-2433 |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.061010 |
| Popis: | Tight control of p63 protein levels must be achieved under differentiation or apoptotic conditions. Here, we describe a new regulatory pathway for the DeltaNp63 alpha protein. We found that MDM2 binds DeltaNp63 alpha in the nucleus promoting its translocation to the cytoplasm. The MDM2 nuclear localization signal is required for Delt Np63 alpha nuclear export and subsequent degradation, whereas the MDM2 ring-finger domain is dispensable. Once exported to the cytoplasm by MDM2, p63 is targeted for degradation by the Fbw7 E3-ubiquitin ligase. Efficient degradation of Delta Np63 alpha by Fbw7 (also known as FBXW7) requires GSK3 kinase activity. By deletion and point mutations analysis we have identified a phosphodegron located in the alpha and beta tail of p63 that is required for degradation. Furthermore, we show that MDM2 or Fbw7 depletion inhibits degradation of endogenous DeltaNp63 alpha in cells exposed to UV irradiation, adriamycin and upon keratinocyte differentiation. Our findings suggest that following DNA damage and cellular differentiation MDM2 and Fbw7 can cooperate to regulate the levels of the pro-proliferative DeltaNp63 alpha protein. |
| Databáze: | OpenAIRE |
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