The growth of M-07e human megakaryocytic leukemia cells is strictly dependent on GM-CSF. In M-07e cells, the GM-CSF receptor (GM-CSF R) is composed of two subunits: a low affinity alpha subunit and a phosphorylated beta subunit, which is constitutively linked to lyn(53/56) protein tyrosine kinase. In this study, The role of lyn kinase in regulating TGF-beta 1-induced apoptosis in M-07e cells was examined. The removal of rhGM-CSF from the culture medium resulted in down-regulation of lyn kinase activity, followed by growth inhibition and programmed cell death. Apoptosis of M-07e cells was accompanied with a massive cleavage of Bcl-2 and Bax proteins into shortened fragments with molecular mass of 22 kD and 18 kD, respectively. Using specific inhibitors, the cleavage of Bcl-2, but not Bax, was found to be processed through activated caspase-3 (CPP32), which is abundantly expressed in M-07e cells. TGF-beta 1 inhibited rhGM-CSF-stimulated cell growth and promoted apoptosis in M-07e cells with a pattern identical to that induced by rhGM-CSF depletion, which included massive cleavage of both Bcl-2 and Bax proteins and inactivation of lyn kinase activity. TGF-beta 1 did not affect the levels of lyn protein or the beta-subunit, neither did it block the interaction between these two components. Also, TGF-beta 1 treatment did not diminish the expression of the alpha subunit in M-07e cells. Our results showed that TGF-beta 1 inhibits cell proliferation and promotes apoptosis in M-07e cells by inactivating the GM-CSF R-associated lyn kinase activity. Further, This study showed that Bcl-2 cleavage by activated CPP32 is a naturally occurring event associated with apoptosis, which is under the regulation of lyn kinase activation.