Tight control of p63 protein levels must be achieved under differentiation or apoptotic conditions. Here, we describe a new regulatory pathway for the ΔNp63α protein. We found that MDM2 binds ΔNp63α in the nucleus promoting its translocation to the cytoplasm. The MDM2 nuclear localization signal is required for ΔNp63α 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 ΔNp63α by Fbw7 (also known as FBXW7) requires GSK3 kinase activity. By deletion and point mutations analysis we have identified a phosphodegron located in the α and β tail of p63 that is required for degradation. Furthermore, we show that MDM2 or Fbw7 depletion inhibits degradation of endogenous ΔNp63α 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 ΔNp63α protein.

MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation / F. Galli, M. Rossi, Y. D'Alessandra, M. De Simone, T. Lopardo, Y. Haupt, O. Alsheich-Bartok, S. Anzi, E. Shaulian, V. Calabrò, G. La Mantia, L. Guerrini. - In: JOURNAL OF CELL SCIENCE. - ISSN 0021-9533. - 123:14(2010 Jul 15), pp. 2423-2433.

MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation

F. Galli;Y. D'Alessandra;M. De Simone;T. Lopardo;L. Guerrini
2010-07-15

Abstract

Tight control of p63 protein levels must be achieved under differentiation or apoptotic conditions. Here, we describe a new regulatory pathway for the ΔNp63α protein. We found that MDM2 binds ΔNp63α in the nucleus promoting its translocation to the cytoplasm. The MDM2 nuclear localization signal is required for ΔNp63α 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 ΔNp63α by Fbw7 (also known as FBXW7) requires GSK3 kinase activity. By deletion and point mutations analysis we have identified a phosphodegron located in the α and β tail of p63 that is required for degradation. Furthermore, we show that MDM2 or Fbw7 depletion inhibits degradation of endogenous ΔNp63α 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 ΔNp63α protein.
DNA damage; Fbw7; MDM2; p63; Active Transport, Cell Nucleus; Animals; Cell Cycle Proteins; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; DNA Damage; Doxorubicin; F-Box Proteins; Humans; Mice; Mutation; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-mdm2; RNA, Small Interfering; Trans-Activators; Transcription Factors; Transcriptional Activation; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Ultraviolet Rays; Cell Biology
Settore BIO/11 - Biologia Molecolare
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/492791
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