Protein kinase C-mediated regulation of the cell cycle

Abstract

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.

Protein kinase C and cancer: what we know and what we do not

“…Not surprisingly, studies from several laboratories highlight a role for PKCε in cell cycle control, specifically in G1 to S progression [165–167]. In addition, PKCε promotes survival in many cell types [6, 168–170].…”

Protein Kinases and Phosphatases in the Control of Cell Fate

“…PKC α is antiproliferative and causes G1 cell-cycle arrest associated with ERK activation and inhibition of p21 and p27 in the intestinal epithelial cells [263]. PKC δ is involved in proliferation defects affecting G1 and G2 phases [264], and is capable of downregulating the expression of cyclins causing cell-cycle arrest in lung adenocarcinoma cells [265, 266]. PKC/PKC α can also induce cell cycle withdrawal and growth suppression in intestinal epithelial cells, an event associated with rapid downregulation of cyclin D1 [267, 268], mediated by activation of 4E-BP1 and inhibition of cap-dependent translation initiation [269].…”

Hallmarks for senescence in carcinogenesis: novel signaling players

“…It has also been established that PKCs inhibit G1/S transition through the induction of the CDK inhibitor p21 via p53-independent mechanisms. PKC activation can also cause a delay in G2/M transition that results from the inhibition in the activity of Cdc2, a key G2/M regulator, and changes in Cdc25-B and C phosphatases that control Cdc2 dephosphorylation [159,160]. Studies in the last years established that PKCd mediates primarily anti-mitogenic and proapoptotic responses.…”

“…Evidence accumulated in the last years revealed that these kinases regulate the cell cycle machinery both through translational and post-translational mechanisms, and distinct roles for individual PKC isozymes have been established in different phases of the cell cycle [159,160]. For example, the PKC activator phorbol 12-myristate 13-acetate (PMA or TPA) can inhibit G1/S progression in numerous cell types, an effect closely associated with the control of pRb phosphorylation and the expression of E2F-regulated genes.…”