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.

Gain-of-function p53 mutants have widespread genomic locations partially overlapping with p63 / E., Martynova; S., Pozzi; Basile, Valentina; D., Dolfini; F., Zambelli; Imbriano, Carol; G., Pavesi; R., Mantovani. - In: ONCOTARGET. - ISSN 1949-2553. - ELETTRONICO. - 3:2(2012), pp. 132-143. [10.18632/oncotarget.447]

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

BASILE, Valentina;IMBRIANO, Carol;
2012

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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Gain-of-function p53 mutants have widespread genomic locations partially overlapping with p63 / E., Martynova; S., Pozzi; Basile, Valentina; D., Dolfini; F., Zambelli; Imbriano, Carol; G., Pavesi; R., Mantovani. - In: ONCOTARGET. - ISSN 1949-2553. - ELETTRONICO. - 3:2(2012), pp. 132-143. [10.18632/oncotarget.447]
E., Martynova; S., Pozzi; Basile, Valentina; D., Dolfini; F., Zambelli; Imbriano, Carol; G., Pavesi; R., Mantovani
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/708892
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