A PHOSPHATIDYLCHOLINE PHOSPHOLIPASE-C INHIBITOR, D609, BLOCKS INTERLEUKIN-3 (IL-3)-INDUCED BCL-2 EXPRESSION BUT NOT C-MYC EXPRESSION IN HUMAN IL-3-DEPENDENT CELLS

Activation of the interleukin-3 (IL-3) receptor is required for the in duction of cell proliferation and suppression of apoptosis in primitiv e hematopoietic progenitor cells. A rapid activation of tyrosine kinas es and a phosphatidylcholine-specific phospholipase C has been observe d in these cells in response to IL-3. The signal transduction cascades regulating cell proliferation and the suppression of apoptosis are po orly understood. Using human IL-3-dependent TF-1 cells, we have found that the tyrosine kinase inhibitor genistein blocks both the IL-3 supp ression of apoptosis and the expression of the cell survival gene bcl- 2. In addition, we have found that D609, a specific inhibitor of phosp hatidylcholine-specific phospholipase C, also inhibits IL-3-induced ex pression of the bcl-2 gene without affecting IL-3-induced tyrosine pho sphorylation. D609 also drove these cells into apoptosis even in the p resence of IL-3. Significantly, genistein inhibited the IL-3 induction of both bcl-2 and c-myc gene. The latter gene is related to the induc tion of cell proliferation. D609, however, blocked the induction only of the cell survival gene bcl-2. Thus, phosphatidylcholine hydrolysis appears linked to the induction of genes related to cell survival. The se data fit with the hypothesis that there is a bifurcation in the sig naling pathways downstream of IL-3 receptor-induced tyrosine phosphory lation. (C) 1998 Academic Press.