The timing and extent of activation of diacylglycerol-responsive protein kinase-cs determines their ability to inhibit or promote platelet-derived growth factor-dependent DNA synthesis

Abstract

In response to natural agonists, such as platelet-derived growth factor (PDGF), diacylglycerol-responsive protein kinase Cs (PKCs) are activated at two distinct times, early and mid G1, and only the late activity is required for the transition into S phase. Surprisingly, the potent PKC activator phorbol 12-myristate 13-acetate (PMA) inhibits DNA synthesis when it is added in mid G1. Here we investigated why different PKC agonists had opposing effects on cell proliferation. We found that the magnitude and timing of PKC activation determined their ability to suppress DNA synthesis. Furthermore, potent activation of PKCs resulted in robust Erk activation and elevation of p21(CIP1). Finally, PMA was unable to block PDGF-dependent cell cycle progression in cells that lack p21(CIP1). These findings indicate that only potent activators of PKC were capable of blocking cell cycle progression, and the mechanism appears to involve an elevation of p21(CIP1).