Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms.
Basal telomerase activity is dependent on expression of the hTERT and hTR genes and upregulation of telomerase gene expression is associated with tumour development. It is therefore possible that signal transduction pathways involved in tumour development and features of the tumour environment itself may influence telomerase gene regulation. The majority of solid tumours contain regions of hypoxia and it has recently been demonstrated that hypoxia can increase telomerase activity by mechanisms that are still poorly defined. Here, we show that hypoxia induces the transcriptional activity of both hTR and hTERT gene promoters. While endogenous hTR expression is regulated at the transcriptional level, hTERT is subject to regulation by alternative splicing under hypoxic conditions, which involves a switch in the splice pattern in favour of the active variant. Furthermore, analysis of the chromatin landscape of the telomerase promoters reveals dynamic recruitment of a transcriptional complex involving the hypoxia-inducible factor-1 transcription factor, p300, RNA polymerase II and TFIIB, to both promoters during hypoxia, which traffics along and remains associated with the hTERT gene as transcription proceeds. These studies show that hTERT and hTR are subject to similar controls under hypoxia and highlight the rapid and dynamic regulation of the telomerase genes in vivo.
Anderson
C J
CJ
Cancer Research UK Beatson Laboratories, Centre for Oncology and Applied Pharmacology, University of Glasgow, Bearsden, Glasgow, UK.
Hoare
S F
SF
Ashcroft
M
M
Bilsland
A E
AE
Keith
W N
WN
D017398:Alternative Splicing; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics*; D012319:RNA Polymerase II / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics*; D016615:Telomere / Q000378:metabolism; D013997:Time Factors; D035581:Transcription Factor TFIIB / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D002843:Chromatin; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035581:Transcription Factor TFIIB; D042461:Vascular Endothelial Growth Factor A; C422952:telomerase RNA; D012313:RNA; D008156:Luciferases; D050880:p300-CBP Transcription Factors; D012319:RNA Polymerase II; D019098:Telomerase