p53 associates with and targets ΔNp63 into a protein degradation pathway

Edward A. Ratovitski, Meera Patturajan, Kenji Hibi, Barry Trink, Kengo Yamaguchi, David Sidransky

Research output: Contribution to journalArticle

Abstract

A human p53 homologue, p63 (p40/p51/p73L/CUSP) that maps to the chromosomal region 3q27-29 was found to produce a variety of transcripts that encode DNA-binding proteins with and without a trans-activation domain (TA- or ΔN-, respectively). The p63 gene locus was found to be amplified in squamous cell carcinoma, and overexpression of ΔNp63 (p40) led to increased growth of transformed cells in vitro and in vivo. Moreover, p63-null mice displayed abnormal epithelial development and germ-line human mutations were found to cause ectodermal dysplasia. We now demonstrate that certain p63 isotypes form complexes with p53. p53 mutations R175H or R248W abolish the association of p53 with p63, whereas V143A or R273H has no effect. Deletion studies suggest that the DNA-binding domains of both p53 and p63 mediate the association. Overexpression of wild type but not mutant (R175H) p53 results in the caspase-dependent degradation of certain ΔNp63 proteins (p40 and ΔNp63α). The association between p53 and ΔNp63 supports a previously unrecognized role for p53 in regulation of ΔNp63 stability. The ability of p53 to mediate ΔNp63 degradation may balance the capacity of ΔNp63 to accelerate tumorigenesis or to induce epithelial proliferation.

Original languageEnglish (US)
Pages (from-to)1817-1822
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number4
DOIs
StatePublished - Feb 13 2001

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Proteolysis
Ectodermal Dysplasia
Germ-Line Mutation
DNA-Binding Proteins
Caspases
Squamous Cell Carcinoma
Carcinogenesis
Mutation
DNA
Growth
Genes
adjuvant P40
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Genetics
  • General

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p53 associates with and targets ΔNp63 into a protein degradation pathway. / Ratovitski, Edward A.; Patturajan, Meera; Hibi, Kenji; Trink, Barry; Yamaguchi, Kengo; Sidransky, David.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 4, 13.02.2001, p. 1817-1822.

Research output: Contribution to journalArticle

Ratovitski, Edward A. ; Patturajan, Meera ; Hibi, Kenji ; Trink, Barry ; Yamaguchi, Kengo ; Sidransky, David. / p53 associates with and targets ΔNp63 into a protein degradation pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 4. pp. 1817-1822.
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