Shi Yan Jun, Ma Zhi Qiang, Tang Jia Wei, Zhao Yang, Wang Xi, Liu Qing, Wang Ping Ping, John Coote, Chen Xue Qun, Du Ji Zeng
Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
WHO Collaborating Center for Research in Human Reproduction, Division of Science and Technology & Foreign Affairs, National Research Institute for Family Planning, Beijing, 100081, China.
Mol Cell Endocrinol. 2017 Oct 15;454:12-22. doi: 10.1016/j.mce.2017.05.031. Epub 2017 May 29.
Hypoxia upregulates hypothalamic corticotrophin releasing hormone (CRH) and its receptor type-1 (CRHR1) expression and activates the HPA axis and induces hypoxic sickness and behavioral change. The transcriptional mechanism by which hypoxia differently regulates CRHR1 expression remains unclear. Here we report hypoxia time-dependently induced biphasic expression of CRHR1mRNA in rat pituitary during different physiological status. Short exposure of gestational dams to hypoxia reduced CRHR1mRNA in the pituitary of P1-P14 male rat offspring. A short- and prolonged-hypoxia evoked biphasic response of CRHR1mRNA characterized initially by decreases and subsequently by persistent increases, mediated by a rapid negative feedback via CRHR1 signaling and positive transcriptional control via NF-κB, respectively. Further analysis of CRHR1 promoter in cultured primary anterior pituitary and AtT20 cells showed that c-Jun/AP-1 delivered negative while HIF-1α and NF-κB delivered positive control of transcription at CRHR1 promoter. The negative and positive inputs are integrated by hypoxic initiation and duration in CRHR1 transcription.
缺氧会上调下丘脑促肾上腺皮质激素释放激素（CRH）及其1型受体（CRHR1）的表达，激活下丘脑-垂体-肾上腺（HPA）轴，引发缺氧性疾病和行为改变。缺氧对CRHR1表达进行差异调节的转录机制尚不清楚。在此，我们报告了在不同生理状态下，缺氧在大鼠垂体中随时间依赖性地诱导CRHR1mRNA的双相表达。孕期母鼠短期暴露于缺氧环境会降低出生后1至14天雄性大鼠子代垂体中的CRHR1mRNA水平。短期和长期缺氧均引发CRHR1mRNA的双相反应，最初表现为下降，随后持续增加，分别由CRHR1信号通路的快速负反馈和NF-κB的正转录控制介导。对原代培养的垂体前叶细胞和AtT20细胞中CRHR1启动子的进一步分析表明，c-Jun/AP-1对CRHR1启动子的转录起负调控作用，而HIF-1α和NF-κB起正调控作用。CRHR1转录中的负向和正向输入由缺氧的起始和持续时间整合。
