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首页> 外文期刊>Molecular and Cellular Biology >Mitogen-Activated Protein Kinase Cascade-Mediated Histone H3 Phosphorylation Is Critical for Telomerase Reverse Transcriptase Expression/Telomerase Activation Induced by Proliferation
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Mitogen-Activated Protein Kinase Cascade-Mediated Histone H3 Phosphorylation Is Critical for Telomerase Reverse Transcriptase Expression/Telomerase Activation Induced by Proliferation

机译：丝裂原激活的蛋白激酶级联介导的组蛋白H3磷酸化对于增殖诱导的端粒酶逆转录酶表达/端粒酶激活至关重要

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Telomerase activity and telomerase reverse transcriptase (hTERT), the key component of the telomerase complex, are tightly proliferation regulated in normal and malignant cells both in vitro and in vivo; however, underlying mechanisms are unclear. In the present study, we identified mitogen-activated protein kinase (MAPK) cascade-mediated histone H3 ser10 phosphorylation to be a molecular link between proliferation and induction of hTERT/telomerase activity. In normal human T lymphocytes and fibroblasts, growth or stress stimuli known to drive H3 phosphorylation through the MAPK signaling induce hTERT expression and/or telomerase activity that was preceded by phosphorylated histone H3 (ser10) at the hTERT promoter. Blockade of the MAPK-triggered H3 phosphorylation significantly abrogates hTERT induction and ser10 phosphorylation at this promoter. However, H3 ser10 phosphorylation alone resulted in low, transient hTERT induction, as seen in fibroblasts, whereas H3 phosphorylation followed by its acetylation at lys14 robustly trans-activated the hTERT gene accompanying constitutive telomerase activity in normal and malignant T cells. H3 acetylation without phosphorylation similarly exerted weak effects on hTERT expression. These results define H3 phosphorylation as a key to hTERT transactivation induced by proliferation and reveal a fundamental mechanism for telomerase regulation in both normal human cells and transformed T cells.
机译：端粒酶活性和端粒酶逆转录酶（hTERT）是端粒酶复合物的关键成分，在体内和体外均在正常和恶性细胞中受到严格的增殖调节。但是，其潜在机制尚不清楚。在本研究中，我们确定有丝分裂原激活的蛋白激酶（MAPK）级联介导的组蛋白H3 ser10磷酸化是增生和hTERT /端粒酶活性的诱导之间的分子联系。在正常的人类T淋巴细胞和成纤维细胞中，已知通过MAPK信号驱动H3磷酸化的生长或应激刺激诱导hTERT表达和/或端粒酶活性，然后在hTERT启动子上磷酸化组蛋白H3（ser10）。 MAPK触发的H3磷酸化的阻断显着消除了该启动子处的hTERT诱导和ser10磷酸化。然而，如在成纤维细胞中所见，单独的H3 ser10磷酸化导致低的瞬时hTERT诱导，而H3磷酸化随后在lys14上的乙酰化则强烈地伴随着 trans 激活 hTERT 基因正常和恶性T细胞中的组成型端粒酶活性没有磷酸化的H3乙酰化同样对hTERT表达产生微弱的影响。这些结果将H3磷酸化定义为由增殖诱导的 hTERT 反式激活的关键，并揭示了正常人细胞和转化T细胞中端粒酶调节的基本机制。

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