Blasco M A, Rizen M, Greider C W, Hanahan D
Cold Spring Harbor Laboratory, New York 11724, USA.
Nat Genet. 1996 Feb;12(2):200-4. doi: 10.1038/ng0296-200.
Telomeres consist of short repeated sequences that are synthesized by telomerase, a ribonucleo-protein DNA polymerase. Telomerase activity is present in many tumours and not detected in many normal tissues. Telomere shortening in human and mouse tissues and primary cell cultures may be due to the absence of telomerase activity. To determine when telomerase is activated during tumour development and progression, we examined telomerase activity and expression of the recently cloned mouse telomerase RNA component (mTR) in two different transgenic mouse models of multi-stage tumorigenesis. These mouse models allow examination of many independent tumours from genetically identical individuals. These mice reproducibly develop pancreatic islet cell carcinoma and squamous cell carcinoma of the skin. In both carcinoma types, we detected telomerase activity only in late-stage tumours; in contrast, we found mTR levels were upregulated in the early preneoplastic stages, and further increased during progression. Surprisingly, mTR levels did not parallel the amount of telomerase activity detected and a subset of tumours lacked telomerase activity and yet expressed telomerase RNA. Regulation of telomerase activity may therefore be separable from expression of its RNA component. These results clearly demonstrate telomerase is activated in late stages of tumour progression, and show for the first time that the initial up regulation of telomerase RNA is an early event, concurrent with the hyperproliferation elicited by viral oncogenes.
端粒由短的重复序列组成，这些序列由端粒酶合成，端粒酶是一种核糖核蛋白DNA聚合酶。端粒酶活性存在于许多肿瘤中，而在许多正常组织中未被检测到。人类和小鼠组织以及原代细胞培养中端粒缩短可能是由于缺乏端粒酶活性。为了确定端粒酶在肿瘤发生和发展过程中何时被激活，我们在两种不同的多阶段肿瘤发生转基因小鼠模型中检测了端粒酶活性以及最近克隆的小鼠端粒酶RNA组分（mTR）的表达。这些小鼠模型允许对来自基因相同个体的许多独立肿瘤进行检测。这些小鼠可重复性地发生胰岛细胞癌和皮肤鳞状细胞癌。在这两种癌症类型中，我们仅在晚期肿瘤中检测到端粒酶活性；相反，我们发现mTR水平在肿瘤发生前的早期阶段上调，并在进展过程中进一步增加。令人惊讶的是，mTR水平与检测到的端粒酶活性量并不平行，并且一部分肿瘤缺乏端粒酶活性但仍表达端粒酶RNA。因此，端粒酶活性的调节可能与其RNA组分的表达是可分离的。这些结果清楚地表明端粒酶在肿瘤进展的晚期被激活，并首次表明端粒酶RNA的最初上调是一个早期事件，与病毒癌基因引发的过度增殖同时发生。
