Identification of two distinct elements mediating activation of telomerase (hTERT) gene expression in association with cell growth in human T cells
Identification of two distinct elements mediating activation of telomerase (hTERT) gene expression in association with cell growth in human T cells
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DOI：
10.1093/intimm/dxh201
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发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Nakamura, M
中科院分区：
文献类型：
--
作者：
Matsumura-Arioka, Y;Ohtani, K;Nakamura, M
淋巴细胞在正常体细胞中是例外的，因为它们像生殖细胞和恶性细胞一样表达高端粒酶活性。我们研究了端粒酶在人T细胞中的诱导与细胞生长的关系。IL-2显著增强PHA激活的人外周血白细胞中端粒酶的限速成分人端粒酶逆转录酶（hTERT）mRNA的表达。在IL-2依赖性人T细胞系Kit 225中检测hTERT基因的分离的5 ′-侧翼序列（-3927-+51）的启动子活性。向静止的Kit 225细胞中加入IL-2诱导hTERT启动子的活化。用hTERT启动子的突变片段进行的报告基因测定进一步揭示了IL-2依赖性激活由+9-+51区域内的两个元件独立介导。这两个元素显示出相似的动力学激活响应IL-2，这正好与G1到S期的细胞周期的转变。有趣的是，在不存在IL-2的情况下，在元件中引入突变会增加静息T细胞中的背景启动子活性。我们的研究结果表明，hTERT启动子可能被抑制的元素和IL-2可能与促进细胞生长的信号去抑制。hTERT启动子的IL-2依赖性激活可能是预防免疫反应期间异常细胞分裂诱导的衰老所必需的。
Lymphocytes are exceptional among normal somatic cells in that they express high telomerase activity like germline and malignant cells. We investigated the induction of telomerase in human T cells in association with cell growth. IL-2 significantly augmented the expression of mRNA for human telomerase reverse transcriptase (hTERT), a rate-limiting component of telomerase, in PHA-activated human peripheral blood leukocytes. An isolated 5'-flanking sequence (-3927-+51) of the hTERT gene was examined for its promoter activity in an IL-2-dependent human T cell line Kit 225. Addition of IL-2 into quiescent Kit 225 cells induced activation of the hTERT promoter. Reporter assays with mutant fragments of the hTERT promoter further revealed that IL-2-dependent activation was independently mediated by two elements within the +9-+51 regions. The two elements showed similar kinetics of activation in response to IL-2, which coincided with the G1 to S phase transition of the cell cycle. Interestingly, introduction of mutation in the elements increased background promoter activities in resting T cells in the absence of IL-2. Our results demonstrate that the hTERT promoter may be suppressed by the elements and IL-2 may signal for de-suppression in association with promotion of cell growth. IL-2-dependent activation of the hTERT promoter may be necessary for prevention from senescence induced by extraordinary cell division during immune reactions.