Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms
Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms
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DOI：
10.1038/sj.onc.1209011
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Keith, WN
中科院分区：
文献类型：
--
作者：
Anderson, CJ;Hoare, SF;Keith, WN
端粒酶的基础活性依赖于hTERT和hTR基因的表达，端粒酶基因的表达上调与肿瘤的发生有关。因此，参与肿瘤发展的信号转导途径和肿瘤环境本身的特点可能会影响端粒酶基因的调控。大多数实体肿瘤都含有缺氧区，最近的研究表明，低氧可以通过尚不明确的机制增加端粒酶的活性。在这里，我们证明了低氧诱导hTR和hTERT基因启动子的转录活性。虽然内源性hTR的表达在转录水平上受到调控，但hTERT在低氧条件下受到选择性剪接的调节，这涉及剪接模式中有利于活性变体的切换。此外，对端粒酶启动子染色质图谱的分析显示，在缺氧过程中，涉及缺氧诱导因子-1转录因子p300、RNA聚合酶II和TFIIB的转录复合体动态地招募到这两个启动子，随着转录的进行，该复合体与hTERT基因一起运输并保持关联。这些研究表明，hTERT和hTR在低氧条件下受到类似的控制，并突出了体内端粒酶基因的快速和动态调节。
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.