A PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR INDUCES A SENESCENT-LIKE GROWTH ARREST IN HUMAN-DIPLOID FIBROBLASTS

The signal transduction cascade initiated by the activation of phospho inositide 3-kinase (PI-3 kinase) is implicated in mitogenic and antiap optotic signaling generated by growth factors in a variety of cell typ es. We have examined the consequences of an inhibition of this pathway in human diploid fibroblasts, We find that a specific PI-3 kinase inh ibitor (LY294002) causes growth arrest in these cells accompanied by c hanges in gene expression that are similar to those seen during cellul ar senescence, A second inhibitor, PD58029, which is specific for the mitogen-activated protein kinase kinase I (MEK-1), also induces a grow th arrest but does not induce the same spectrum of gene expression, Th e pattern of gene expression in the presence the MEK-1 inhibitor is si milar to that seen during growth arrest induced by serum starvation, T he specific phenotypic changes seen following inhibition of PI-3 kinas e are: an increase in beta-galactosidase activity; a decrease in EPC-I gene expression; and a dramatic increase in collagenase gene expressi on, Thus, growth arrest with a PI-3 kinase inhibitor induces a senesce nt-like phenotype that is not seen when cells are growth arrested by e ither serum starvation or a MEK-1 inhibitor.