Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells.
Trancriptional regulation of the human telomerase reverse transcriptase (hTERT) gene, encoding the catalytic protein of human telomerase, plays a critical role in the activation of the enzyme during cell immortalization and tumorigenesis. However, the molecular mechanisms involved in the regulation of hTERT expression are still not fully understood. We have previously cloned and characterized the genomic sequences and promoter of the hTERT gene. Here, we provide evidence that histone deacetylation is involved in the repression of hTERT in human cells. Inhibition of histone deacetylases by trichostatin A in telomerase-negative cells resulted in activation of telomerase activity and up-regulation of hTERT mRNA. Transient transfection experiments with a reporter under control of the hTERT promoter indicated that this promoter can be activated by trichostatin A. Finally, our results show that repression of the hTERT promoter by the Mad protein requires histone deacetylase activity, whereas de-repression by trichostatin A is independent of the E-boxes located in its core region.
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Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
Bacchetti
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D000107:Acetylation / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012313:RNA; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C079439:MXD1 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; C422952:telomerase RNA; C012589:trichostatin A; D012313:RNA; D019098:Telomerase; D006655:Histone Deacetylases