c-Abl stabilizes p73 by a phosphorylation-augmented interaction

Kelvin K C Tsai, Zhi Min Yuan

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

The proapoptotic function of c-Abl is in part mediated by its functional interaction with p73, a p53 homologue. Although it has been shown that c-Abl-mediated p73 activation in response to genotoxic stress is associated with an increase of p73 protein levels, the underlying mechanism remains unclear. We show here that c-Abl increases the cellular p73 abundance through a mode of posttranslational regulation. Analogous to its functional activation of p73, the kinase activity is essential for c-Abl to upregulate p73 protein levels. Analysis of phosphorylation-resistant mutants of p73 reveals that the effect of c-Abl is mediated by its direct phosphorylation on the p73 protein. Consequence to the phosphorylation is a marked increase of the association between c-Abl and p73 via the binding of tyrosine-phosphorylated p73 to the c-Ahl Sre homology 2 (SH2) domain. Of functional importance of this phosphorylation-induced interaction in p73 stabilization is the demonstration that expression of a c-Ahl SH2 domain peptide, which impedes phosphorylation-dependent association, results in an almost complete abrogation of c-Abl-dependent p73 accumulation. Importantly, expression of the c-Abl SH2 domain peptide also leads to an efficient inhibition of cisplatin-induced accumulation of endogenous p73, highlighting the biological significance. In keeping with its retained phosphorylation sites, the NH2-terminal truncated (ΔN) isoforms of p73, which are antiapoptotic, are also phosphorylated and stabilized by c-Abl, suggesting a possibility that c-Abl contributes to either pro- or antiapoptotic process depending on the expression profile of p73 isoforms.

Original languageEnglish
Pages (from-to)3418-3424
Number of pages7
JournalCancer Research
Volume63
Issue number12
Publication statusPublished - Jun 15 2003
Externally publishedYes

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Phosphorylation
Protein Isoforms
Cisplatin
DNA Damage
Tyrosine
Phosphotransferases
Up-Regulation
Tumor Protein p73
Protein Domains

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

c-Abl stabilizes p73 by a phosphorylation-augmented interaction. / Tsai, Kelvin K C; Yuan, Zhi Min.

In: Cancer Research, Vol. 63, No. 12, 15.06.2003, p. 3418-3424.

Research output: Contribution to journalArticle

Tsai, Kelvin K C ; Yuan, Zhi Min. / c-Abl stabilizes p73 by a phosphorylation-augmented interaction. In: Cancer Research. 2003 ; Vol. 63, No. 12. pp. 3418-3424.
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