A novel apoptotic cascade mediated by CDK4 in rat pheochromocytoma PC12 cells.

Apoptosis induced by serum withdrawal in pheochromocytoma PC12 cells is promoted by overexpression of cyclin-dependent kinase 4 (CDK4). We compared CDK4-promoted apoptosis with that induced by serum withdrawal alone in PC12 cells. Protein synthesis inhibitors did not prevent apoptosis in parental cells, but prevented the promotion of apoptosis by CDK4 overexpression. Nerve growth factor, basic-fibroblast growth factor, and Bcl-2 proteins protected both parental and CDK4-overexpressing cells from apoptosis. However, insulin-like growth factor-I and Bcl-X(L) protein only partially inhibited apoptosis in the CDK4-overexpressing cells. Bcl-2 or Bcl-X(L) had no significant effect on CDK4 kinase activity in both cell lines. These results suggest a novel CDK4-mediated apoptotic cascade which is normally restrained, but which is activated by CDK4 overexpression. This apoptotic cascade should eventually converge with the cascade induced by serum withdrawal in normal PC12 cells. We discuss the interactions among these apoptotic cascades and the points where anti-apoptotic agents act.