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Molecular and Cellular Biology, December 2002, p. 8659-8668, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8659-8668.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Complex Transcriptional Effects of p63 Isoforms: Identification of Novel Activation and Repression Domains{dagger}

Pamela Ghioni,1 Fabrizio Bolognese,1 Pascal H. G. Duijf,2 Hans van Bokhoven,2 Roberto Mantovani,3 and Luisa Guerrini1*

Dipartimento di Genetica e Biologia dei Microrganismi, Milan,1 Dipartimento di Biologia Animale, 41100 Modena, Italy,3 Department of Human Genetics, Nijmegen, The Netherlands2

Received 21 February 2002/ Returned for modification 6 May 2002/ Accepted 23 September 2002

p63 is a transcription factor structurally related to the p53 tumor suppressor. The C-terminal region differs from p53's in that it contains a sterile alpha motif (SAM) domain and is subject to multiple alternative splicings. The N-terminal region is present in the transactivation (TA) and {Delta}N configurations, with the latter lacking the transcriptional activation domain 1. Single amino acid substitutions and frameshift mutations of p63 cause the human ankyloblepharon ectodermal dysplasia clefting (AEC) or ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndromes. We have systematically compared the activities of the wild-type p63 isoforms and of the natural mutants in activation and repression assays on three promoters modulated by p53. We found that p63 proteins with an altered SAM domain or no SAM domain—the ß isoforms, the EEC frameshift mutant, and the missense AEC mutations—all showed a distinctly higher level of activation of the MDM2 promoter and decreased repression on the HSP70 promoter. Fusion of SAM to the GAL4 DNA-binding domain repressed a heterologous promoter. A second activation domain, TA2, corresponding to exons 11 to 12, was uncovered by comparing the activation of {Delta}N isoforms on natural promoters and in GAL4 fusion systems. In colony formation assays, the AEC mutants, but not the EEC frameshift, were consistently less efficient in suppressing growth, in both the TA version and the {Delta}N version, with respect to their p63{alpha} counterparts. These data highlight the modularity of p63, identifying the SAM domain as a dominant transcriptional repression module and indicating that the AEC and EEC frameshift mutants are characterized by a subversion of the p63 transcriptional potential.

* Corresponding author. Mailing address: Dipartimento di Genetica e Biologia dei Microrganismi, Via Celoria 26, 20133 Milano, Italy. Phone: 02-5031-5000. Fax: 02-5031-5044. E-mail: luisa.guerrini{at}unimi.it. {dagger} Luisa dedicates this work to the memory of Giusi.

Molecular and Cellular Biology, December 2002, p. 8659-8668, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8659-8668.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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