A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblasts.
The signal transduction cascade initiated by the activation of phosphoinositide 3-kinase (PI-3 kinase) is implicated in mitogenic and antiapoptotic signaling generated by growth factors in a variety of cell types. We have examined the consequences of an inhibition of this pathway in human diploid fibroblasts. We find that a specific PI-3 kinase inhibitor (LY294002) causes growth arrest in these cells accompanied by changes in gene expression that are similar to those seen during cellular senescence. A second inhibitor, PD58029, which is specific for the mitogen-activated protein kinase kinase 1 (MEK-1), also induces a growth arrest but does not induce the same spectrum of gene expression. The pattern of gene expression in the presence the MEK-1 inhibitor is similar to that seen during growth arrest induced by serum starvation. The specific phenotypic changes seen following inhibition of PI-3 kinase are: an increase in beta-galactosidase activity; a decrease in EPC-1 gene expression; and a dramatic increase in collagenase gene expression. Thus, growth arrest with a PI-3 kinase inhibitor induces a senescent-like phenotype that is not seen when cells are growth arrested by either serum starvation or a MEK-1 inhibitor.
Tresini
M
M
Center for Gerontological Research, Department of Pathology, MCP-Hahnemann School of Medicine, Allegheny University, Philadelphia, Pennsylvania 19129, USA.
Mawal-Dewan
M
M
Cristofalo
V J
VJ
Sell
C
C
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020929:Mitogen-Activated Protein Kinase Kinases; D001616:beta-Galactosidase