TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF H1 HISTONE GENE-EXPRESSION BY 1-BETA-D-ARABINOFURANOSYLCYTOSINE

Recent studies have demonstrated that 1-beta-D-arabinofuranosylcytosin e (ara-C) activates the transcription of the jun/fos early response ge nes in human myeloid leukemia cells. The basis for ara-C-induced contr ol of gene expression remains unclear. However, down-regulation of H-1 histone mRNA levels has been reported as one of the earliest changes in specific gene expression associated with ara-C treatment. In this r eport, we describe the mechanisms responsible for H-1 histone expressi on by this agent. Treatment of HL-60 cells with ara-C resulted in a de crease in H-1 histone mRNA levels that was detectable by 15 min. In co ntrast, this down-regulation by ara-C was completely blocked by treatm ent of the cells with cycloheximide. Nuclear run-on analyses demonstra ted that ara-C treatment is associated with inhibition of H-1 histone gene transcription. The results also demonstrate that cycloheximide ab rogates the transcriptional down-regulation by ara-C but alone has no detectable effect. We also show that ara-C treatment is associated wit h a decrease in stability of the H-1 histone transcript and that this effect is also reversed by inhibition of protein synthesis. Taken toge ther, these findings demonstrate that ara-C regulates H-1 histone expr ession at both the transcriptional and posttranscriptional levels. The results also indicate that control of this gene by ara-C involves the activation of at least two signaling events that require de novo prot ein synthesis.