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A p38-dependent pathway regulates ΔNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes

Oncogene volume 24, pages 6970–6975 (2005)Cite this article

Abstract

The p53 protein plays a pivotal role in determining the quality of the response to DNA damage through its transcriptional activity. Upon DNA damage, p53 is activated by post-translational modifications, binds its cognate sequences on the promoters of its target genes and stimulates transcription. In proliferating keratinocytes, the activity of p53 is blunted by its inhibitor ΔNp63α. Here, we describe a novel mechanism through which ΔNp63 functions in order to prevent the survival and propagation of ultraviolet (UV)-damaged keratinocytes. We found that UVB stimulation induces the rapid phosphorylation of ΔNp63, which precedes ΔNp63 transcriptional downregulation and protein degradation, which is mediated by the p38 MAPK. Phosphorylated ΔNp63 has a lower affinity for p53REs and detaches from cell cycle arrest and apoptotic promoters, thus allowing the rapid activation of p53-dependent transcriptional apoptotic program.

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Acknowledgements

This work is dedicated to the memory of Andrea Pocci: a friend, a man who fought cancer. We thank Dr Saverio Minucci for critically reading the manuscript. This work was supported by grants from Italian Ministry of Health (Prog finalizzati), AIRC, ECFP6 (Contract 503576) to AC and from Telethon (Project E1325), AIRC, ECFP6 (contract 503576), MIUR FIRB, COFIN 2004 to ML and COFIN 2003 and Italian Ministry of health Regione Lazio to SC.

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Authors and Affiliations

  1. Department of Dermatology, University of Rome, ‘Tor Vergata’, Viale Oxford 81, Rome, 00133, Italy

    Marina Papoutsaki, Mauro Lanza, Barbara Marinari, Sergio Chimenti & Antonio Costanzo

  2. Fondazione A Cesalpino, CRS Regina Elena Cancer Center, Via delle Mesii D'oro, 00153, Rome, Italy

    Francesca Moretti, Massimo Levrero & Antonio Costanzo

  3. Laboratory of Muscle Biology, Muscle Gene Expression Group, NIMAS, National Institutes of Health, Bethesda, MD, USA

    Vittorio Sartorelli

  4. Dipartimento di Genetica e Biologia dei Microrganismi, University of Milan, Italy

    Luisa Guerrini

  5. Department of Internal Medicine, University of Rome, ‘La Sapienza’, Rome, Italy

    Massimo Levrero

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  1. Marina Papoutsaki
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  2. Francesca Moretti
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Correspondence to Massimo Levrero or Antonio Costanzo.

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Papoutsaki, M., Moretti, F., Lanza, M. et al. A p38-dependent pathway regulates ΔNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes. Oncogene 24, 6970–6975 (2005). https://doi.org/10.1038/sj.onc.1208835

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