Oncotarget

Research Papers:

∆N-P63α and TA-P63α exhibit intrinsic differences in transactivation specificities that depend on distinct features of DNA target sites.

Paola Monti _, Yari Ciribilli, Alessandra Bisio, Giorgia Foggetti, Ivan Raimondi, Paola Campomenosi, Paola Menichini, Gilberto Fronza and Alberto Inga

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Oncotarget. 2014; 5:2116-2130. https://doi.org/10.18632/oncotarget.1845

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Abstract

Paola Monti1,*, Yari Ciribilli2,*, Alessandra Bisio*2, Giorgia Foggetti1, Ivan Raimondi2,3, Paola Campomenosi3,4, Paola Menichini1, Gilberto Fronza1,**, Alberto Inga2,**

1 Mutagenesis Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy;

2 Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy;

3 Department of Biotechnology and Life Sciences, DBSV, University of Insubria, Varese, Italy;

4 The Protein Factory, Centro Interuniversitario di Ricerca in Biotecnologie Proteiche, Politecnico di Milano, ICRM-CNR Milano and Università degli Studi dell’Insubria, Varese, Italy

* These authors contributed equally to this work

** These authors share last authorship

Correspondence:

Alberto Inga, email:

Gilberto Fronza, email:

Keywords: TP63; transcription; transactivation specificity; TP73; TP53; Response Element

Received: February 5, 2014 Accepted: March 21, 2014 Published: March 23, 2014

Abstract

TP63 is a member of the TP53 gene family that encodes for up to ten different TA and ∆N isoforms through alternative promoter usage and alternative splicing. Besides being a master regulator of gene expression for squamous epithelial proliferation, differentiation and maintenance, P63, through differential expression of its isoforms, plays important roles in tumorigenesis. All P63 isoforms share an immunoglobulin-like folded DNA binding domain responsible for binding to sequence-specific response elements (REs), whose overall consensus sequence is similar to that of the canonical p53 RE. Using a defined assay in yeast, where P63 isoforms and RE sequences are the only variables, and gene expression assays in human cell lines, we demonstrated that human TA- and ∆N-P63α proteins exhibited differences in transactivation specificity not observed with the corresponding P73 or P53 protein isoforms. These differences 1) were dependent on specific features of the RE sequence, 2) could be related to intrinsic differences in their oligomeric state and cooperative DNA binding, and 3) appeared to be conserved in evolution. Sicen genotoxic stress can change relative ratio of TA- and ∆N-P63α protein levels, the different transactivation specificity of each P63 isoform could potentially influence cellular responses to specific stresses.


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