Article

c-Abl tyrosine kinase selectively regulates p73 nuclear matrix association

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2003; 278(36):34475-82. DOI: 10.1074/jbc.M301051200
Source: PubMed

ABSTRACT p73 is a structural and functional homologue of the p53 tumor-suppressor protein. Like p53, p73 is activated in response to DNA-damaging insults to induce cell cycle arrest or apoptosis. Under these conditions p73 is tyrosine-phosphorylated by c-Abl, a prerequisite modification for p73 to elicit cell death in fibroblasts. In this study we report that in response to ionizing radiation, p73 undergoes nuclear redistribution and becomes associated with the nuclear matrix. This association is c-Abl-dependent because it was not observed in cells that are defective in c-Abl kinase activation. Moreover, STI-571, a specific c-Abl kinase inhibitor, is sufficient to block significantly p73 alpha nuclear matrix association. The observed c-Abl dependence of nuclear matrix association was recapitulated in the heterologous baculovirus system. Under these conditions p73 alpha but not p53 is specifically tyrosine-phosphorylated by c-Abl. Moreover, the phosphorylated p73 alpha is predominantly found in association with the nuclear matrix. Thus, in response to ionizing radiation p73 is modified in a c-Abl-dependent manner and undergoes nuclear redistribution and translocates to associate with the nuclear matrix. Our data describe a novel mechanism of p73 regulation.

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    • "Initial studies demonstrated that c-Abl is associated with p73 through SH3 domain of c- Abl and PY motif of p73, and directly phosphorylates p73 at Tyr-99 in response to CDDP and ionizing radiation [60] [61] [62]. Phosphorylated form of p73 underwent nuclear redistribution and became associated with the nuclear matrix [63]. c-Abl-mediated phosphorylation of p73 at Tyr-99 increased its stability and enhanced its transcriptional as well as proapoptotic activity. "
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