αl-Adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes
αl-Adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes
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DOI：
10.1016/s0378-1119(02)00924-1
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发表时间：
2002-09-04
期刊：
影响因子：
3.5
通讯作者：
Stewart, AFR
中科院分区：
文献类型：
--
作者：
Maeda, T;Sepulveda, J;Stewart, AFR
心肌锚蛋白重复序列（CARP）是肥大心肌细胞中被多种信号通路激活的核转录辅助因子。由于CARP已被报道为一种转录共抑制因子，其在肥厚过程中的激活可能有助于基因表达的失调，从而导致心力衰竭。在这里，我们发现α(1)-肾上腺素能信号激活大鼠心肌细胞中CARP mRNA的表达。为了研究α(1)-肾上腺素能信号如何激活CARP基因，克隆了小鼠CARP启动子的660 bp片段。先前的报道表明，小鼠鲤鱼启动子依赖于GATA4转录因子，而人类鲤鱼启动子依赖于转录增强因子-1 （TEF-1）。TEF-1和GATA4转录因子是已知的α(1)-肾上腺素能信号的介质，通过凝胶迁移试验确定，它们在多个位点与小鼠CARP启动子结合。这些位点在小鼠和人类启动子之间高度保守，表明它们在两者中都具有重要的功能。突变分析表明，心肌细胞中CARP启动子的基础活性需要TEF-1因子的结合。然而，TEF-1因子的过表达不能增强鲤鱼启动子对i -肾上腺素能刺激的反应。另一方面，α(1)-肾上腺素能反应被GATA4过表达增强。综上所述，我们的研究结果表明，α(1)-肾上腺素能信号在一定程度上通过转录因子GATA4调节心肌细胞中的CARP表达。(C) 2002 Elsevier Science B.V.版权所有
Cardiac ankyrin repeat protein (CARP) is a nuclear transcription cofactor that is activated by multiple signaling pathways in hypertrophic cardiac myocytes. Since CARP has been reported to be a transcriptional co-repressor, its activation during hypertrophy might contribute to the deregulation of gene expression leading to heart failure. Here, we found that alpha(1)-adrenergic signaling activates CARP mRNA expression in rat cardiac myocytes. To examine how alpha(1)-adrenergic signaling activates the CARP gene, a 660 bp fragment of the mouse CARP promoter was cloned. Previous reports suggested that the mouse CARP promoter was dependent on the GATA4 transcription factor whereas the human CARP promoter was dependent on transcriptional enhancer factor-1 (TEF-1). TEF-1 and GATA4 transcription factors, known mediators of alpha(1)-adrenergic signaling, bound to the mouse CARP promoter at several sites as determined by gel mobility shift assays. These sites are highly conserved between the mouse and human promoters, suggesting that they are functionally important in both. Mutation analysis showed that binding of TEF-1 factors is required for basal activity of the CARP promoter in cardiac myocytes. However, over-expression of TEF-1 factors could not potentiate the response of the CARP promoter to a I-adrenergic stimulation. On the other hand, the alpha(1)-adrenergic response was potentiated by GATA4 over-expression. Taken together, our results demonstrate that alpha(1)-adrenergic signaling regulates CARP expression in cardiac myocytes, in part through the transcription factor GATA4. (C) 2002 Elsevier Science B.V. All rights reserved.