Abstract
The protein kinase C (PKC) family consists of multiple isoforms that are involved in the regulation of diverse cellular responses. Suppression of PKC induces growth arrest in various types of cells. However, the underlying molecular mechanisms have not been thoroughly investigated. In this report, we demonstrated that the concurrent inhibition, rather than separate inhibition, of phorbol ester-dependent PKC alpha and theta isoforms is crucial for the induction of G1 cell cycle arrest and that this negative cell cycle regulation is via p53-independent mechanisms. PKC suppression-mediated growth arrest is associated with the induction of cell cycle inhibitor p21WAF1/CIP1 and the occurrence of hypophosphorylated Rb. The G1 checkpoint induced by the suppression of PKC occurs not only in murine Swiss3T3 but also in p53-deficient cells and human lung cancer cells containing mutated p53. Luciferase and nuclear run-off assays demonstrated that p21WAF1/CIP1 is, in part, transcriptionally regulated in response to the suppression of PKC alpha and theta. However, the stability of p21 mRNA is also augmented after the addition of PKC alpha and theta antisense oligonucleotides, indicating the involvement of post-transcriptional mechanisms in p21WAF1/CIP1 expression. These data suggest the existence of a cell cycle checkpoint pathway regulated by PKC alpha and theta isoforms. Furthermore, our findings support the notion that G1 checkpoint control can be restored in tumor cells containing abnormal p53, by targeting the PKC-regulated p21WAF1/CIP1 induction.
Highlights
Diacylglycerol and directly activate the enzyme [5, 6]
We demonstrated that the concurrent inhibition, rather than separate inhibition, of phorbol ester-dependent protein kinase C (PKC) ␣ and isoforms is crucial for the induction of G1 cell cycle arrest and that this negative cell cycle regulation is via p53-independent mechanisms
We have demonstrated that phorbol ester-dependent PKC ␣ and isoforms act as prosurvival factors, counteracting Fas-mediated apoptotic signaling [43]
Summary
Diacylglycerol and directly activate the enzyme [5, 6]. Phorbol esters elicit a variety of physiological responses in different target cells, including modulation of ion fluxes, secretory responses, changes in gene expression, and inhibition of growth [7,8,9,10,11,12]. One of the effects of persistent suppression of PKC activity by either persistent high dose of phorbol esters or PKC inhibitors is to arrest cells in the G1 phase of the cell cycle [15,16,17]. The mechanisms of such growth suppression are not yet clear. The action of PKC activity has been demonstrated to be linked to cell growth and tumor promotion, the mechanism of PKC suppression-induced cell cycle arrest is not clear. It is important to understand the underlying mechanisms of the growth arrest mediated by PKC suppression and its impact on cells, especially on tumor cells containing nonfunctional or deleted p53
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