
<ArticleTitle><prot>E2F-1</prot> represses transcription of the human <prot><prot>telomerase</prot> reverse transcriptase</prot> gene.</ArticleTitle>
<AbstractText>The ends of human chromosomes (telomeres) lose up to 200 bp of DNA per cell division. Chromosomal shortening ultimately leads to senescence and death in normal cells. Many human carcinoma lines are immortal in vitro, suggesting that these cells have a mechanism for maintaining the ends of their chromosomes. <prot>Telomerase</prot> is a ribonucleoprotein complex that synthesizes telomeric DNA onto chromosomes using its RNA component as template. <prot>Telomerase</prot> activity is found in most tumor cells, but is absent from normal cells. Little is known about how normal human cells repress <prot>telomerase</prot> (<prot>hTERT</prot>) gene expression. Mice carrying an <prot>E2F-1</prot> null mutation develop a variety of malignant tumors, suggesting that this transcription factor has a tumor suppressor function. To determine mechanisms by which <prot>E2F-1</prot> suppresses tumor formation, we examined the role of this transcription factor in regulation of the <prot>hTERT</prot> promoter in human cells. We identified two putative <prot>E2F-1</prot>-binding sites proximal to the transcriptional start site of the <prot>hTERT</prot> promoter. Mutation of these sites produced dramatic increases in promoter activity. Overexpression of <prot>E2F-1</prot> but not a mutant <prot>E2F-1</prot> repressed <prot>hTERT</prot> promoter activity in reporter gene assays. This repression was abolished by mutation of the <prot>E2F-1</prot>-binding sites in the <prot>hTERT</prot> promoter. Human cancer cell lines stably overexpressing <prot>E2F-1</prot> exhibited decreased <prot>hTERT</prot> mRNA expression and <prot>telomerase</prot> activity. We conclude that <prot>E2F-1</prot> has an atypical function as a transcriptional repressor of the <prot>hTERT</prot> gene in human cells.</AbstractText>
