Linking Protein Kinase C to Cell‐Cycle Control

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Abstract
Protein kinase C (PKC) isoenzymes are involved in diverse cellular functions, including differentiation, growth control, tumor promotion, and cell death. In recent years, evidence has began to emerge suggesting a role for PKC in cell cycle control. A paper published recently, demonstrating a functional link between PKC and cell cycle control in yeast (Marini, N. J., Meldrum, E., Buehrer, B., Hubberstey, A. V., Stone, D. E., Traynor‐Kaplan, A. & Reed, S. I. (1996) EMBO J. 15, 3040–3052), strengthens this data. Thus, the existence of cell‐cycle‐regulated pathways involving PKC in both yeast and mammals indicate that PKC may be a conserved regulator of cell cycle events that links signal transduction pathways and the cell‐cycle machinery. In this paper, we will review current data on the cell cycle components that are targets for PKC regulation. PKC enzymes appear to operate as regulators of the cell cycle at two sites, during G1 progression and G2/M transition. In G1, the overall effect of PKC activation is inhibition of the cell cycle at mid to late G1. This cell cycle inhibition correlates with a blockage in the normal phosphorylation of the tumor suppressor retinoblastoma Rb protein, presumably through an indirect mechanism. The reduced activity of the cyclin‐dependent kinase, Cdk2, appears to be the major effect of PKC activation in various cell systems. This may also underlie the inhibition of Rb phosphorylation exhibited by PKC activation. Several mechanisms were described in different studies on the regulation of Cdk2 activity by PKC; reduced Cdk‐activating kinase activity, diminished expression of the Cdk2 partners cyclins E or A, and the increased expression of the cyclin‐dependent inhibitors, p21WAF1 and p27KIPI, which are capable of binding to cyclin/Cdk2 complexes. PKC enzymes were also shown to play a role in G2/M transition. Among the suggested mechanisms is suppression of Cdc2 activity. However, most of the published data strongly implicate PKC in lamin B phosphorylation and nuclear envelope disassembly.

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