PRO-APOPTOTIC EFFECT OF THE C-ABL TYROSINE KINASE IN THE CELLULAR-RESPONSE TO 1-BETA-D-ARABINOFURANOSYLCYTOSINE

Treatment of cells with the antimetabolite 1-beta-D-arabinofuranosylcy tosine (ara-C) and other genotoxic agents is associated with activatio n of the c-Abl protein tyrosine kinase. The functional role of c-Abl i n the response to DNA damage, however, remains unclear. The present st udies demonstrate that cells expressing a dominant negative, kinase-in active c-Abl (K-R) are resistant to killing by ara-C. The expression o f c-Abl (K-R) blocked ara-C-induced apoptosis by a mechanism that is a t least in part independent of the p53 tumor suppressor. Cells null fo r c-Abl also exhibited resistance to induction of apoptosis. These fin dings provide support for a pro-apoptotic function of c-Abl in the res ponse to certain genotoxic drugs.