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 induction of cell proliferation and suppression of apoptosis in primitive hematopoietic progenitor cells. A rapid activation of tyrosine kinases and a phosphatidylcholine-specific phospholipase C has been observed in these cells in response to IL-3. The signal transduction cascades regulating cell proliferation and the suppression of apoptosis are poorly understood. Using human IL-3-dependent TF-1 cells, we have found that the tyrosine kinase inhibitor genistein blocks both the IL-3 suppression of apoptosis and the expression of the cell survival gene bcl-2. In addition, we have found that D609, a specific inhibitor of phosphatidylcholine-specific phospholipase C, also inhibits IL-3-induced expression of the bcl-2 gene without affecting IL-3-induced tyrosine phosphorylation. D609 also drove these cells into apoptosis even in the presence 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 induction 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. These data fit with the hypothesis that there is a bifurcation in the signaling pathways downstream of IL-3 receptor-induced tyrosine phosphorylation.
Mufson
R A
RA
Holland Laboratory for Biomedical Science, American Red Cross, Rockville, Maryland 20855, USA.
Gubina
E
E
Rinaudo
M
M
Baxter
G
G
D017209:Apoptosis; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007377:Interleukin-3 / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology*; D009636:Norbornanes; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000378:metabolism
D001952:Bridged-Ring Compounds; D003470:Culture Media; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D008934:Mitogens; D009636:Norbornanes; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D013859:Thiocarbamates; D013871:Thiones; D014443:Tyrosine; C046498:tricyclodecane-9-yl-xanthogenate; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C