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Molecular and Cellular Biology, December 2002, p. 8601-8611, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8601-8611.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A C-Terminal Inhibitory Domain Controls the Activity of p63 by an Intramolecular Mechanism

Zach Serber,1 Helen C. Lai,1 Annie Yang,2 Horng D. Ou,1 Martina S. Sigal,3 Alexander E. Kelly,1 Beatrice D. Darimont,4 Pascal H. G. Duijf,5 Hans van Bokhoven,5 Frank McKeon,2 and Volker Dötsch3*

Graduate Group in Biophysics,1 Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143,3 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,2 Department of Biology, University of Oregon, Eugene, Oregon 97403,4 Department of Human Genetics, University Medical Centre Nijmegen, 6500 HB Nijmegen, The Netherlands5

Received 7 March 2002/ Returned for modification 8 May 2002/ Accepted 23 September 2002

The human genome is far smaller than originally estimated, and one explanation is that alternative splicing creates greater proteomic complexity than a simple count of open reading frames would suggest. The p53 homologue p63, for example, is a tetrameric transcription factor implicated in epithelial development and expressed as at least six isoforms with widely differing transactivation potential. In particular, p63{alpha} isoforms contain a 27-kDa C-terminal region that drastically reduces their activity and is of clear biological importance, since patients with deletions in this C terminus have phenotypes very similar to patients with mutations in the DNA-binding domain. We have identified a novel domain within this C terminus that is necessary and sufficient for transcriptional inhibition and which acts by binding to a region in the N-terminal transactivation domain of p63 homologous to the MDM2 binding site in p53. Based on this mechanism, we provide a model that explains the transactivation potential of homo- and heterotetramers composed of different p63 isoforms and their effect on p53.

* Corresponding author. Mailing address: Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143. Phone: (415) 502-7050. Fax: (415) 476-0688. E-mail: volker{at}picasso.ucsf.edu.

Molecular and Cellular Biology, December 2002, p. 8601-8611, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8601-8611.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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