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Transcriptional and posttranscriptional regulation of H1 histone gene expression by 1-beta-D-arabinofuranosylcytosine

R Datta, S Kharbanda and DW Kufe

Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.

Recent studies have demonstrated that 1-beta-D-arabinofuranosylcytosine (ara-C) activates the transcription of the jun/fos early response genes in human myeloid leukemia cells. The basis for ara-C-induced control of gene expression remains unclear. However, down-regulation of H1 histone mRNA levels has been reported as one of the earliest changes in specific gene expression associated with ara-C treatment. In this report, we describe the mechanisms responsible for H1 histone expression by this agent. Treatment of HL-60 cells with ara-C resulted in a decrease in H1 histone mRNA levels that was detectable by 15 min. In contrast, this down-regulation by ara-C was completely blocked by treatment of the cells with cycloheximide. Nuclear run-on analyses demonstrated that ara-C treatment is associated with inhibition of H1 histone gene transcription. The results also demonstrate that cycloheximide abrogates the transcriptional down-regulation by ara-C but alone has no detectable effect. We also show that ara-C treatment is associated with a decrease in stability of the H1 histone transcript and that this effect is also reversed by inhibition of protein synthesis. Taken together, these findings demonstrate that ara-C regulates H1 histone expression 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 protein synthesis.

Volume 41, Issue 1, pp. 64-68, 01/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




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