C-ABL TYROSINE KINASE CAN MEDIATE TUMOR-CELL APOPTOSIS INDEPENDENTLY OF THE RB AND P53 TUMOR SUPPRESSORS

Tumor cells frequently lack the p53 tumor suppressor because p53 media tes apoptosis in these cells. We report here that c-Abl, and to a grea ter extent a c-Abl mutant defective for DNA-binding, can provoke progr ammed cell death in p53-deficient tumor cells. Tyrosine kinase mutant K290R is less cytotoxic, In contrast, a C-terminal deletion mutant tha t lacks the RNA polymerase II (PolII)/actin interaction domain, fails to mediate apoptosis unless expressed to very high levels. Cytotoxicit y is overcome by coexpression of the apoptosis antagonist E1B 19K prot ein, and partially overcome by full-length retinoblastoma protein (Rb) or the C pocket fragment of Rb (SE Delta) that associates with c-Abl, c-Abl is also highly toxic to Saos-2 cells that are deficient for bot h Rb and p53, indicating that cell death is not the result of inhibiti on through c-Abl of the anti-apoptotic function of Rb. Finally, p53 an d c-Abl combined induce apoptosis stronger than either protein alone. Unlike Abl-mediated cell death, apoptosis by p53 is antagonized effici ently only by full-length Rb with intact A/B pocket but not by SE Delt a. Mutant p53 inhibits apoptosis by p53 but not c-Abl, Thus, c-Abl wit h intact kinase and PolIII actin-binding domains can affect tumor cell survival independently of Rb and p53.