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
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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