CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death.
CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death.
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DOI：
10.3390/ijms161126067
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发表时间：
2015-11-24
影响因子：
5.6
通讯作者：
Huang CY
中科院分区：
文献类型：
--
作者：
Chen WK;Kuo WW;Hsieh DJ;Chang HN;Pai PY;Lin KH;Pan LF;Ho TJ;Viswanadha VP;Huang CY
在缺氧过程中，各种转录因子会改变基因的表达。胰岛素样生长因子-II(IGF2)是由低氧诱导的，它与IGF2受体IGF2R结合，其作用类似于G蛋白偶联受体，可能导致病理性肥大或激活线粒体介导的细胞凋亡途径。环磷酸腺苷(CAMP)反应元件结合蛋白(CREB)是第二信使调控转录的核心蛋白，在心肌细胞存活途径中起着关键作用。在这项研究中，我们发现在H9c2心肌细胞中，IGF2R水平以时间依赖的方式被上调，但被CREB表达下调。在H9c2成肌细胞中过表达CREB可抑制低氧诱导的IGF2R表达水平，减少细胞凋亡。凝胶位移分析进一步表明，CREB与IGF2R的启动子序列结合。通过荧光素酶活性测定，我们进一步观察到CREB抑制IGF2R启动子活性。这些结果表明，CREB通过与IGF2R启动子结合而抑制IGF2R的表达，进而抑制低氧条件下IGF2R信号诱导的H9c2心肌细胞的凋亡。
During hypoxia, gene expression is altered by various transcription factors. Insulin-like growth factor-II (IGF2) is known to be induced by hypoxia, which binds to IGF2 receptor IGF2R that acts like a G protein-coupled receptor, might cause pathological hypertrophy or activation of the mitochondria-mediated apoptosis pathway. Cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) is central to second messenger-regulated transcription and plays a critical role in the cardiomyocyte survival pathway. In this study, we found that IGF2R level was enhanced in H9c2 cardiomyoblasts exposed to hypoxia in a time-dependent manner but was down-regulated by CREB expression. The over-expression of CREB in H9c2 cardiomyoblasts suppressed the induction of hypoxia-induced IGF2R expression levels and reduced cell apoptosis. Gel shift assay results further indicated that CREB binds to the promoter sequence of IGF2R. With a luciferase assay method, we further observed that CREB represses IGF2R promoter activity. These results suggest that CREB plays an important role in the inhibition of IGF2R expression by binding to the IGF2R promoter and further suppresses H9c2 cardiomyoblast cell apoptosis induced by IGF2R signaling under hypoxic conditions.