Protein kinase C-mediated regulation of the cell cycle

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth/cell cycle progression and differentiation. Increasing evidence from studies using in vitro and in vivo systems points to PKC as a key regulator of critical cell cycle transitions, including cell cycle entry and exit and the G(1) and G(2) checkpoints. PKC-mediated control of these transitions can be negative or positive, depending on the timing of PKC activation during the cell cycle and on the specific PKC isozymes involved. Most of the mechanistic information available relates to the involvement of this enzyme family in negative regulation of these transitions. Accumulating data indicate that a major target for PKC-mediated inhibition of cell cycle progression is the Cip/Kip cyclin-dependent kinase (cdk) inhibitor p21(waf1/cip1). Increased expression of p21(waf1/cip1) blocks cdk2 activity in G(1) phase, leading to hypophosphorylation of the retinoblastoma protein and inhibition of cell cycle progression into S phase. In G(2), p21(waf1/cip1) expression blocks cdc2/cyclin B activity, likely through an indirect mechanism involving inhibition of the cdk2/cyclin A complex, and prevents progression into M phase. PKC signaling can also activate a coordinated program of pocket protein regulation leading to cell cycle withdrawal into G(0). The molecular events underlying positive regulation of cell cycle progression by PKC signaling remain poorly understood, although there is evidence for a role of the enzyme in promoting G(2)-->M progression by phosphorylating lamin B at sites involved in nuclear lamina disassembly. Understanding of the mechanisms underlying PKC-mediated control of the cell cycle is beginning to provide important insight into its role in uncontrolled cell growth and transformation.