title: c-Abl stabilizes p73 by a phosphorylation-augmented interaction.
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 up-regulate 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-Abl Src homology 2 (SH2) domain. Of functional importance of this phosphorylation-induced interaction in p73 stabilization is the demonstration that expression of a c-Abl 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 NH(2)-terminal truncated (Delta N) 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.
authors.affiliation: Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Kelvin K C
authors.initials: KK
authors.lastname: Tsai
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000502:physiology*; D002945:Cisplatin / Q000037:antagonists & inhibitors; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D018909:src Homology Domains
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin