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.
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.
Kharbanda
S
S
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Datta
R
R
Kufe
D
D
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D016590:Aphidicolin; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun; D011519:Proto-Oncogenes; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D013449:Sulfonamides; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*
D004268:DNA-Binding Proteins; D004224:Diterpenes; D007546:Isoquinolines; D010879:Piperazines; D016755:Proto-Oncogene Proteins c-jun; D012334:RNA, Neoplasm; D013449:Sulfonamides; D014157:Transcription Factors; D003561:Cytarabine; D003609:Dactinomycin; D016590:Aphidicolin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D003513:Cycloheximide; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C