Requirement for Mdm2 in the survival effects of Bcr-Abl and interleukin 3 in hematopoietic cells

The p53/Mdm2 pathway plays an important role in the induction of cell cycle arrest or apoptosis in response to genotoxic stress. Both the oncogene Ber -Abi and physiological growth factors such as interleukin (IL)-3 can modula te the outcome of cellular exposure to DNA damage. To determine whether Ber -Abl and growth factors can affect the p53/Mdm2 pathway, we studied the exp ression of Mdm2 in the IL-3-dependent pre-B cell line BaF3 and its bcr-abl- transfected derivative BaF(3)p185 after IL-3 deprivation or treatment with the c-Abl tyrosine kinase inhibitor STI571. We found that both growth facto r withdrawal and inhibition of Bcr-Abl kinase lead to a down-regulation of Mdm2 preceding the induction of apoptosis. Apoptotic cell death induced by STI571 is partially dependent on p53. The early decrease of Mdm2 protein wa s not attributable to transcriptional regulation or to caspase-mediated cle avage. On the other hand, it could be completely blocked by the proteasomal inhibitor lactacystin. Targeted down-regulation of Mdm2 protein by antisen se oligode-oxynucleotides overcame the survival effects of IL-3 and Ber-Abl and resulted in accelerated apoptosis. Taken together, survival signals pr ovided either by physiological growth factors or by oncogenic Bcr-Abl can p ositively regulate Mdm2, whereas Mdm2 ablation can reduce cell survival. Th ese findings imply that, similarly to physiological growth factors such as IL-3, Bcr-Abl can promote cell survival through modulating the p53-Mdm2 pat hway.