Counter C M, Meyerson M, Eaton E N, Ellisen L W, Caddle S D, Haber D A, Weinberg R A
Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
Oncogene. 1998 Mar 5;16(9):1217-22. doi: 10.1038/sj.onc.1201882.
The expression of telomerase, the enzyme that synthesizes telomeric DNA de novo, is suppressed in normal somatic human cells but is reactivated during tumorigenesis. This reactivation appears to arrest the normal loss of telomeric DNA incurred as human cells divide. Since continual loss of telomeric DNA is predicted to eventually limit cell proliferation, activation of telomerase in cancer cells may represent an important step in the acquisition of the cell immortalization which occurs during tumor progression. The telomerase holoenzyme is composed of both RNA and protein subunits. In humans, mRNA expression of hTERT (hEST2), the candidate telomerase catalytic subunit gene, appears to parallel the levels of telomerase enzyme activity, suggesting that induction of hTERT is necessary and perhaps sufficient for expression of telomerase activity in tumor cells. To test this model directly, we ectopically expressed an epitope-tagged version of hTERT in telomerase-negative cells and show that telomerase activity was induced to levels comparable to those seen in immortal telomerase-positive cells and that the expressed hTERT protein was physically associated with the cellular telomerase activity. We conclude that synthesis of the hTERT telomerase subunit represents the rate-limiting determinant of telomerase activity in these cells and that this protein, once expressed, becomes part of the functional telomerase holoenzyme.
端粒酶可重新合成端粒DNA，在正常人体体细胞中，该酶的表达受到抑制，但在肿瘤发生过程中会重新激活。这种重新激活似乎阻止了人体细胞分裂时端粒DNA的正常丢失。由于预计端粒DNA的持续丢失最终会限制细胞增殖，癌细胞中端粒酶的激活可能是肿瘤进展过程中细胞永生化的一个重要步骤。端粒酶全酶由RNA和蛋白质亚基组成。在人类中，候选端粒酶催化亚基基因hTERT（hEST2）的mRNA表达似乎与端粒酶活性水平平行，这表明hTERT的诱导对于肿瘤细胞中端粒酶活性的表达是必要的，甚至可能是充分的。为了直接验证该模型，我们在端粒酶阴性细胞中异位表达了一个带有表位标签的hTERT版本，结果显示端粒酶活性被诱导至与永生化端粒酶阳性细胞中所见水平相当，并且所表达的hTERT蛋白与细胞端粒酶活性存在物理关联。我们得出结论，hTERT端粒酶亚基的合成是这些细胞中端粒酶活性的限速决定因素，并且该蛋白一旦表达，就会成为功能性端粒酶全酶的一部分。
