Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms
Autor: | W N Keith, Alan Bilsland, C J Anderson, S F Hoare, Margaret Ashcroft |
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Rok vydání: | 2005 |
Předmět: |
Vascular Endothelial Growth Factor A
Chromatin Immunoprecipitation Cancer Research Telomerase DNA Complementary Time Factors Transcription Genetic Blotting Western RNA polymerase II Transfection Polymerase Chain Reaction Cell Line Tumor Gene expression Genetics Humans p300-CBP Transcription Factors Telomerase reverse transcriptase RNA Processing Post-Transcriptional Hypoxia Luciferases Promoter Regions Genetic Molecular Biology Transcription factor Regulation of gene expression biology Genetic Variation Promoter Exons Telomere Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Chromatin Cell biology DNA-Binding Proteins Gene Expression Regulation Neoplastic Alternative Splicing Gene Expression Regulation Transcription Factor TFIIB biology.protein RNA RNA Polymerase II Transcription factor II B Signal Transduction |
Zdroj: | Oncogene. 25:61-69 |
ISSN: | 1476-5594 0950-9232 |
Popis: | 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. |
Databáze: | OpenAIRE |
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