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Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

Oncogene volume 30, pages 922–932 (2011)Cite this article

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Abstract

Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor.

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Acknowledgements

We thank V Yang (Emory University, USA) and C Ishioka (Tohoru U Jp) for gift of the KLF4-Luciferase vector and mutant p53 vectors, respectively. We thank K Vousden and P Muller (Beatson I, UK) for information on the p53 siRNA oligonucleotide. This work was supported by grants from the European Union (EPISTEM LSHB-CT-2005-019067), MIUR and Associazione Italiana per la Ricerca sul Cancro (to RM).

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  1. Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano Via Celoria 26, Milano, Italy

    N Cordani, S Pozzi, E Martynova, S Borrelli, M A Viganò & R Mantovani

  2. Istituto di Scienze Dermatologiche, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Università degli Studi di Milano, Milano, Italy

    D Fanoni & E Berti

  3. Dipartimento di Chirurgia Plastica-Banca della Cute, Ospedale CTO, Torino, Italy

    D Alotto & C Castagnoli

  4. Università di Milano-Bicocca, Milano, Italy

    E Berti

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Cordani, N., Pozzi, S., Martynova, E. et al. Mutant p53 subverts p63 control over KLF4 expression in keratinocytes. Oncogene 30, 922–932 (2011). https://doi.org/10.1038/onc.2010.474

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