Regulation of c-jun gene expression in HL-60 leukemia cells by 1-.beta.-D-arabinofuranosylcytosine. Potential involvement of a protein kinase C dependent mechanism

Abstract

1-beta-D-Arabinofuranosylcytosine (ara-C) is an effective chemotherapeutic agent that incorporates into DNA and results in DNA fragmentation. Recent work has demonstrated that ara-C transiently induces expression of the c-jun immediate early response gene. The present studies in HL-60 myeloid leukemia cells extend these findings by demonstrating that the increase in c-jun mRNA levels at 6 h of ara-C treatment is regulated by a transcriptional mechanism. In contrast, the subsequent down-regulation of c-jun expression is controlled by a posttranscriptional decrease in the stability of the c-jun transcripts. Previous work in phorbol ester treated cells has indicated that c-jun expression is regulated by the activation of protein kinase C. The present results demonstrate that protein kinase C activity is increased in ara-C-treated cells. This increase was maximal at 60 min and remained detectable through 6 h of ara-C exposure. Moreover, the induction of c-jun transcripts by ara-C was inhibited by the isoquinolinesulfonamide derivative H7, but not by HA1004, suggesting that this effect is mediated by protein kinase C. Ara-C-induced c-jun expression was also inhibited by staurosporine, another inhibitor of protein kinase C. Taken together, these results indicate that the cellular response to ara-C includes the activation of protein kinase C and that ara-C potentially induces c-jun transcription by a protein kinase C dependent signaling mechanism.