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PMID: 12446779 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Molecular and cellular biology ·Vol. 22 ·No. 24 ·2002-12-00 ·Pages 8601-11

Serber Z, Lai HC, Yang A, Ou HD, Sigal MS, Kelly AE, Darimont BD, Duijf PH, Van Bokhoven H, McKeon F, Dötsch V

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, 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.

MeSH Terms
Amino Acid Sequence Animals Binding Sites Cell Nucleus/metabolism DNA-Binding Proteins Gene Expression Regulation Genes, Reporter Genes, Tumor Suppressor Humans Membrane Proteins Mice Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Peptides/genetics,metabolism Phenotype Phosphoproteins/genetics,metabolism Protein Isoforms/genetics,metabolism Protein Structure, Quaternary Protein Structure, Secondary Protein Structure, Tertiary Recombinant Fusion Proteins Repressor Proteins/genetics,metabolism Sequence Alignment Trans-Activators/genetics,metabolism Transcription Factors Transcription, Genetic Tumor Suppressor Protein p53/genetics,metabolism Tumor Suppressor Proteins
Chemicals
CKAP4 protein, human DNA-Binding Proteins Membrane Proteins Peptides Phosphoproteins Protein Isoforms Recombinant Fusion Proteins Repressor Proteins TP63 protein, human Trans-Activators Transcription Factors Trp63 protein, mouse Tumor Suppressor Protein p53 Tumor Suppressor Proteins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Serber Zach
Graduate Group in Biophysics, University of California San Francisco, San Francisco, California 94143, USA.
Lai Helen C
Yang Annie
Ou Horng D
Sigal Martina S
Kelly Alexander E
Darimont Beatrice D
Duijf Pascal H G
Van Bokhoven Hans
McKeon Frank
Dötsch Volker
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.24.8601-8611.2002
Published
2002-12-00
Pages
8601-11
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC139862
Subset
IM
Grants
NIGMS NIH HHS · T32 GM008284 · United States
NIGMS NIH HHS · GM08284 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.24.8601-8611.2002 PMC Full Text View journal details
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