Oncotarget

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Gain-of-function p53 mutants have widespread genomic locations partially overlapping with p63.

Elena Martynova, Silvia Pozzi, Valentina Basile, Diletta Dolfini, Federico Zambelli, Carol Imbriano, Giulio Pavesi and Roberto Mantovani _

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Oncotarget. 2012; 3:132-143. https://doi.org/10.18632/oncotarget.447

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Abstract

Elena Martynova*,1, Silvia Pozzi*,1, Valentina Basile2, Diletta Dolfini1, Federico Zambelli1, Carol Imbriano2, Giulio Pavesi1, Roberto Mantovani1

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

2 Dipartimento di Biologia, Università degli Studi di Modena e Reggio Emilia, Modena, Italy

* Denotes equal contribution

Received: February 10, 2012; Accepted: February 10, 2012; Published: February 22, 2012;

Keywords: mutant p53, p63, keratinocytes

Correspondence:

Roberto Mantovani,

Abstract

p53 and p63 are transcription factors -TFs- playing master roles in the DNA-damage response and in the development and maintenance of pluristratified epithelia, respectively. p53 mutations are common in epithelial tumors and HaCaT keratinocytes harbor two p53 alleles -H179Y and R282Q- with gain-of-function (GOF) activity. Indeed, functional inactivation of mutp53 affects the growth rate of HaCaT. We investigated the strategy of mutp53, by performing ChIP-Seq experiments of mutp53 and p63 and analyzed the transcriptome after mutp53 inactivation. Mutp53 bind to 7135 locations in vivo, with a robust overlap with p63. De novo motifs discovery recovered a p53/p63RE with high information content in sites bound by p63 and mutp53/p63, but not by mutp53 alone: these sites are rather enriched in elements of other TFs. The HaCaT p63 locations are only partially overlapping with those of normal keratinocytes; importantly, and enriched in mutp53 sites which delineate a functionally different group of target genes. Our data favour a model whereby mutp53 GOF mutants act both by tethering growth-controlling TFs and highjacking p63 to new locations.

 


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