1601

The ubiquitously expressed c-Abl tyrosine kinase localizes to the cytoplasm and nucleus. Nuclear c-Abl is activated by diverse genotoxic agents and induces apoptosis; however, the mechanisms responsible for nuclear targeting of c-Abl remain unclear. Here we show that cytoplasmic c-Abl is targeted to the nucleus in the DNA damage response. The results demonstrate that c-Abl is sequestered in the cytoplasm by binding to 14-3-3 proteins. Phosphorylation of c-Abl on Thr-735 functions as a site for direct binding to 14-3-3. We also show that, in response to DNA damage, activation of the c-Jun N-terminal kinase (JNK) induces phosphorylation of 14-3-3 and release of c-Abl from 14-3-3. In concert with these results, expression of an unphosphorylated 14-3-3 mutant attenuates DNA damage-induced nuclear import of c-Abl and apoptosis. Furthermore, we found that cytoplasmic oncogenic Abl kinase, Bcr-Abl, also translocates to the nucleus upon exposure to genotoxic stress and the nuclear targeting of Bcr-Abl is regulated by, at least in part, 14-3-3. These findings indicate that 14-3-3 is a pivotal regulator of intracellular Abl kinase localization and the apoptotic response to genotoxic stress.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA