A C-terminal inhibitory domain controls the activity of p63 by an intramolecular mechanism

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

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Abstract

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, p63α 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.

Original languageEnglish (US)
Pages (from-to)8601-8611
Number of pages11
JournalMolecular and cellular biology
Volume22
Issue number24
DOIs
StatePublished - Dec 1 2002

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Serber, Z., Lai, H. C., Yang, A., Ou, H. D., Sigal, M. S., Kelly, A. E., Darimont, B. D., Duijf, P. H. G., Van Bokhoven, H., McKeon, F., & Dötsch, V. (2002). A C-terminal inhibitory domain controls the activity of p63 by an intramolecular mechanism. Molecular and cellular biology, 22(24), 8601-8611. https://doi.org/10.1128/MCB.22.24.8601-8611.2002