Linking Protein Kinase C to Cell‐Cycle Control

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 G 2 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 studieq 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, p2lWAF1 and p27K'P', which are capable of binding to cyclidCdk2 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.Keywords: protein kinase C ; cell cycle; cyclin ; cyclin-dependent kinase; Cdk inhibitor; retinoblastoma protein; p53 protein; phorbol ester; GUS transition; G2/M transition. Protein kinase C and growth regulationThe term protein kinase C (PKC) stands for a group of at least ten serinehhreonine kinases that are characterized by a high degree of similarity in their catalytic kinase domains and cysteine-rich regions [l-41. The PKC family is subdivided into three groups; the classical PKC members (a, p, y) are Ca2+ and diacylglycerol-dependent, the novel PKCs (6, E , q and d) are Ca2+-independent but diacylglycerol-dependent and the atypical PKCs ([ and 2) are not activated by Ca*+ and diacylglycerol in vitro [3, 41. This may account for the multiplicity and diversity of the cellular activities implicated to be mediated by PKC, sinceCorrespondence to

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

“…Furthermore, treatment with selective PKC inhibitors abolished ERK activation and markedly attenuated DNA synthesis in response to AVP. These results suggest that PKC could play different roles in cell proliferation at different stages of the cell cycle (44). Collectively, our results indicate that receptor-mediated PKC activation, as induced by AVP, transduces mitogenic signals leading to DNA synthesis and cell proliferation in IEC-18 cells.…”

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

“…Caco-2 transfectants were trypsinized, and replated at lower confluency to induce a large fraction to enter S phase. As shown in Table 1 (Livneh and Fishman, 1997;Fishman et al, 1998;Black, 2000), we attribute TPA-induced G1 slowing in our Caco-2 transfectants to the activation of PKC-d, since the nontargeted isoforms did not differ in expression among parental, EV, and PKC-d transfectants (Cerda et al, 2001). By 48 h of phorbol ester treatment, there was decreased proliferation in EV and PKC-d transfectants that we speculate arises from downregulation of growth-promoting PKC isoforms that result in an overall decrease in cellular proliferation (Figure 1).…”

Protein Kinase D Potentiates DNA Synthesis and Cell Proliferation Induced by Bombesin, Vasopressin, or Phorbol Esters in Swiss 3T3 Cells

“…The DAG-regulated PKC isoforms all bind phorbol esters and are major cellular targets for this class of tumor promoter (16). PKCs, which have been implicated in the regulation of a wide range of biological responses including cell proliferation and carcinogenesis (17,18), play a pivotal role in neuropeptidemediated mitogenesis (2,19). Despite the recognized importance of PKCs in mitogenic signal transduction, the downstream targets that mediate PKC-induced cell proliferation remain largely undefined.…”