Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT)
Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT)
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DOI：
10.1128/mcb.24.13.6076-6083.2004
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发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Isaka, K
中科院分区：
文献类型：
--
作者：
Nishi, H;Nakada, T;Isaka, K
缺氧发生在妊娠早期胎盘的发育过程中，与滋养层细胞分化和hTERT表达诱导端粒酶活性有关。我们试图确定hTERT在低氧条件下表达的调节机制。我们发现低氧诱导因子1α(HIF-1α)和hTERT在胎盘中的表达随着胎龄的增加而减少，并且在妊娠的主要并发症--先兆子痫胎盘中过度表达。缺氧不仅能反式激活hTERT启动子的活性，还能增强内源性hTERT的表达。HTERT启动子区域在-165和+51之间包含两个HIF-1共有基序，体外报告分析表明这些基序是hTERT被HIF-1反式激活所必需的。引入针对HIF-1的反义寡核苷酸可减少缺氧时hTERT的表达，表明缺氧对hTERT的上调是通过HIF-1直接介导的。我们的结果提供了令人信服的证据，表明HIF-1对hTERT启动子活性的调节代表了滋养层细胞在低氧条件下生长的一种机制，并表明这可能是一种在各种人类疾病中对低氧的普遍反应，包括通过上调端粒酶来抵抗癌症治疗。
Hypoxia occurs during the development of the placenta in the first trimester and correlates with both trophoblast differentiation and the induction of telomerase activity through hTERT expression. We sought to determine the mechanism of regulation of hTERT expression during hypoxia. We show that hypoxia-inducible factor 1alpha (HIF-1alpha) and hTERT expression in the human placenta decrease with gestational age and that these are overexpressed in preeclamptic placenta, a major complication of pregnancy. Hypoxia not only transactivates the hTERT promoter activity but also enhances endogenous hTERT expression. The hTERT promoter region between -165 and +51 contains two HIF-1 consensus motifs, and in vitro reporter assays show that these are essential for hTERT transactivation by HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT expression during hypoxia, indicating that upregulation of hTERT by hypoxia is directly mediated through HIF-1. Our results provide persuasive evidence that the regulation of hTERT promoter activity by HIF-1 represents a mechanism for trophoblast growth during hypoxia and suggests that this may be a generalized response to hypoxia in various human disorders including resistance to cancer therapeutics by upregulating telomerase.