Transcriptional and posttranscriptional regulation of H1 histone gene expression by 1-beta-D-arabinofuranosylcytosine.
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.
Datta
R
R
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Kharbanda
S
S
Kufe
D W
DW
D003513:Cycloheximide / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000502:physiology; D006657:Histones / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D006657:Histones; D012333:RNA, Messenger; D003561:Cytarabine; D003609:Dactinomycin; D003513:Cycloheximide