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

Biochemistry. 1991 Aug 13;30(32):7947-52. doi: 10.1021/bi00246a011.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Aphidicolin
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / physiology
  • Cycloheximide / pharmacology
  • Cytarabine / pharmacology*
  • DNA-Binding Proteins / genetics*
  • Dactinomycin / pharmacology
  • Diterpenes / pharmacology
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Isoquinolines / pharmacology
  • Kinetics
  • Leukemia, Promyelocytic, Acute
  • Piperazines / pharmacology
  • Protein Kinase C / metabolism*
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogenes*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / isolation & purification
  • Sulfonamides*
  • Transcription Factors / genetics*
  • Transcription, Genetic / drug effects*


  • DNA-Binding Proteins
  • Diterpenes
  • Isoquinolines
  • Piperazines
  • Proto-Oncogene Proteins c-jun
  • RNA, Neoplasm
  • Sulfonamides
  • Transcription Factors
  • Cytarabine
  • Dactinomycin
  • Aphidicolin
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • N-(2-guanidinoethyl)-5-isoquinolinesulfonamide
  • Cycloheximide
  • Protein-Tyrosine Kinases
  • Protein Kinase C