DNA-binding and transactivation activities are essential for TAp63 protein degradation

Ying, H. Q., Chang, D. L. F., Zheng, H. W., McKeon, F., Xiao, Z. X. J. (July 2005) DNA-binding and transactivation activities are essential for TAp63 protein degradation. Molecular and Cellular Biology, 25 (14). pp. 6154-6164. ISSN 0270-7306

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URL: http://www.ncbi.nlm.nih.gov/pubmed/15988026
DOI: 10.1128/mcb.25.14.6154-6164.2005

Abstract

The p53-related p63 gene encodes six isoforms with differing N and C termini. TAp63 isoforms possess a transactivation domain at the N terminus and are able to transactivate a set of genes, including some targets downstream of p53. Accumulating evidence indicates that TAp63 plays an important role in regulation of cell proliferation, differentiation, and apoptosis, whereas transactivation-inert Delta Np63 functions to inhibit p63 and other p53 family members. Mutations in the p63 gene that abolish p63 DNA-binding and transactivation activities cause human diseases, including ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndrome. In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndrome are DNA binding deficient, transactivation inert, and highly stable. We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activities and that p63 is degraded in a proteasome-dependent, MDM2-independent pathway. In addition, the N-terminal transactivation domain of p63 is indispensable for its protein degradation. Furthermore, the wild-type TAp63 gamma can act in trans to promote degradation of mutant TAp63 gamma defective in DNA binding, and the TA domain deletion mutant of TAp63 gamma inhibits transactivation activity and stabilizes the wild-type TAp63 protein. Taken together, these data suggest a feedback loop for p63 regulation, analogous to the p53-MDM2 feedback loop.

Item Type: Paper
Uncontrolled Keywords: P53 HOMOLOG P63 TRANSCRIPTIONAL ACTIVATION MDM2 UBIQUITIN P73 STABILITY DOMAIN EXPRESSION APOPTOSIS CELL Biochemistry & Molecular Biology Cell Biology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > DNA binding protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > TAp63
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: July 2005
Date Deposited: 22 Aug 2014 19:43
Last Modified: 22 Aug 2014 19:43
PMCID: PMC1168832
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30707

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