Zhao J Q, Hoare S F, McFarlane R, Muir S, Parkinson E K, Black D M, Keith W N
CRC Department of Medical Oncology, University of Glasgow, UK.
Oncogene. 1998 Mar 12;16(10):1345-50. doi: 10.1038/sj.onc.1201892.
Variation in telomerase activity is correlated with cellular senescence and tumour progression. However, although the enzymatic activity of telomerase has been well studied, very little is known about how expression of telomerase genes is regulated in mammalian cells. We have therefore cloned the promoter regions of the human (hTR), and mouse, (terc), telomerase RNA genes in order to identify the regulatory elements controlling telomerase RNA gene transcription. 1.76 kb encompassing the hTR gene promoter region was sequenced, as was 4 kb encompassing the terc promoter. No significant sequence similarity could be detected in comparisons between human and mouse 5'-regions, flanking the transcribed sequences. However, both the human and mouse telomerase RNA genes are within CpG islands and may therefore be under the regulation of DNA methylation. Transient expression of hTR-reporter gene constructs in HeLa and GM847 cells identified the elements responsible for promoter activity are contained in a 231 bp region upstream of the transcriptional start site. Transient expression of terc-reporter gene constructs in Swiss3T3 and A9 cells identified the elements responsible for promoter activity are contained in a 73 bp region upstream of the transcriptional start site. These studies have implications for novel transcription targeted cancer therapies.
端粒酶活性的变化与细胞衰老和肿瘤进展相关。然而，尽管端粒酶的酶活性已得到充分研究，但对于哺乳动物细胞中端粒酶基因的表达是如何调控的却知之甚少。因此，我们克隆了人类（hTR）和小鼠（terc）端粒酶RNA基因的启动子区域，以确定控制端粒酶RNA基因转录的调控元件。对包含hTR基因启动子区域的1.76 kb片段以及包含terc启动子的4 kb片段进行了测序。在转录序列侧翼的人类和小鼠5'区域之间的比较中，未检测到明显的序列相似性。然而，人类和小鼠端粒酶RNA基因均位于CpG岛内，因此可能受DNA甲基化调控。hTR报告基因构建体在HeLa和GM847细胞中的瞬时表达表明，负责启动子活性的元件位于转录起始位点上游231 bp区域内。terc报告基因构建体在Swiss3T3和A9细胞中的瞬时表达表明，负责启动子活性的元件位于转录起始位点上游73 bp区域内。这些研究对新型转录靶向癌症治疗具有重要意义。
