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35. p21WAF1 Expression by Activator of Protein Kinase C is Regulated Mainly at Post-transcriptional Level in Cells Lacking p53: Important Role of RNA Stabilization
Makoto Akashi, Misao Hachiya, Sakae Tanosaki and Yoshiko Kawase
Keywords: p21WAF1, p53, protein kinase C, mitogen-activated protein kinase
p21WAF1 inhibits cyclin/cycline-dependent kinase (Cdk) complexes, causing cell cycle arrest. p21WAF1 contains p53-binding sites in its promoter; and expression of p21WAF1 is inducedfibroblasts WI38 with PMA also induced the accumulation of p21WAF1 without affecting p53 levels. However, PMA did not increase levels of p21WAF1 mRNA in cells with either their PKC or mitogen-activated protein kinase (MAPK) pathway blocked. Furthermore, treatment of cells with various derivatives of phorbol esters which activate PKC resulted in the induction of p21WAF1 in SKOV-3 cells. In contrast, phorbol esters, which are unable to activate PKC, failed to induce p21WAF1 expression. PMA increased the transcriptional rate of p21WAF1 and activated the transcription of a luciferase reporter gene controlled by the p21 promoter with or without a p53 consensus binding sequence placed in the SKOV-3 cells. On the other hand, PMA markedly stabilized p21WAF1 mRNA; the half-life (t1/2) of p21WAF1 in PMA-treated cells was more than 8 hours as compared to less than 1 hour in untreated cells. These findings provide evidence that the PKC pathway induces expression of p21WAF1 independent of p53. Our present study also suggests that the accumulation of p21WAF1 transcripts by PMA occurs mainly at the post-transcriptional level.
Publications:
Akashi M, Osawa Y, Koeffler HP, Hachiya M.: Biochem. J., 337, 607-616, 1999.
