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

• DOI: 10.1128/mcb.22.24.8601-8611.2002
• Publication Date: 2002-11-21T23:43:48Z
• Authors: Zach Serber; Helen C. Lai; Annie Yang; Horng D. Ou; Martina S. Sigal; Alexander E. Kelly; Beatrice D. Darimont; Pascal H. G. Duijf; Hans van Bokhoven; Frank McKeon; Volker Dötsch
• Keywords: Models, Molecular; 0301 basic medicine; 572; Elucidation of hereditary disorders and their molecular diagnosis; Molecular Sequence Data; Protein Structure, Secondary; Mice; 03 medical and health sciences; Genes, Reporter; Animals; Humans; Protein Isoforms; Genes, Tumor Suppressor; Amino Acid Sequence; Protein Structure, Quaternary; Molecular Biology; Cell Nucleus; Binding Sites; Membrane Proteins; Cell Biology; Phosphoproteins; DNA-Binding Proteins; Phenotype; Gene Expression Regulation; Mutagenesis, Site-Directed; Opheldering van erfelijke ziekten en hun moleculaire diagnostiek; Peptides

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, p63alpha 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.