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Nucleic Acids Research 2006 34(3):928-938; doi:10.1093/nar/gkj477
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Published online 9 February 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63

Barbara Testoni and Roberto Mantovani*

Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano Via Celoria 26, 20133 Milano, Italy

*To whom correspondence should be addressed. Tel: +39 02 50315005; Fax: +39 02 50315044; Email: mantor{at}unimi.it

Received October 7, 2005. Revised November 30, 2005. Accepted January 12, 2006.

p63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon–Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly–Ectodermal dysplasia–Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G2/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and {Delta}Np63{alpha} are associated in vivo and a conserved {alpha}-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. {Delta}Np63{alpha}, but not the AEC mutants repress CCAAT-dependent transcription of G2/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G2/M promoters, while normally present on 14-3-3{sigma}, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G2/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations.


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