Transcriptional activation by stimulating protein 1 and post-transcriptional repression by muscle-specific microRNAs of IKS-encodina genes and potential implications in regional heterogeneity of their expressions (Retracted article. See vol. 227, pg. 877, 2012)
Transcriptional activation by stimulating protein 1 and post-transcriptional repression by muscle-specific microRNAs of IKS-encodina genes and potential implications in regional heterogeneity of their expressions (Retracted article. See vol. 227, pg. 877, 2012)
复制标题
DOI：
10.1002/jcp.21030
复制
发表时间：
2007-08-01
影响因子：
5.6
通讯作者：
Wang, Zhiguo
中科院分区：
文献类型：
--
作者：
Luo, Xiaobin;Xiao, Jiening;Wang, Zhiguo
在心脏细胞中，KCNQI与KCNEI组装并形成通道复合物，构成慢延迟整流电流i - k。KCNQI和KCNEI的表达具有区域异质性，并随心脏病理状态的变化而变化。本研究旨在揭示KCNQI和KCNEI基因转录和转录后调控表达的分子机制，并揭示其空间分布异质性的分子机制。我们克隆了KCNQI基因的5'侧区，并确定了KCNQI基因的转录起始位点。我们对KCNQI和KCNEI的核心启动子进行了鉴定，发现刺激蛋白（Sp 1）通过与KCNQI和KCNEI核心启动子区域的Sp I顺式作用元件相互作用，是KCNQI和KCNEI的共同反激活子。我们还鉴定了这些基因的3‘非翻译区（3’ utr），并通过实验分别建立了KCNQI和KCNEI作为肌肉特异性microrna miR-133和miR-1抑制的靶标。我们证实了KCNQI和KCNEI在三个轴（室间、壁间和顶基）上分布的空间异质性，以及这些基因mRNA和蛋白表达的差异。我们还发现SpI和miR-l/miR- 133在心脏中的表达存在特征性的区域差异。我们的研究揭示了miRNA细胞功能的一个新方面，并表明i - ks编码基因KCNQI和KCNEI的表达是通过转录因子调控和miRNA抑制而动态平衡的。SpI和miR-I/miR-133的异质性可以解释KCNQI和KCNEI mRNA和蛋白表达的区域差异和差异。
In cardiac cells, KCNQI assembles with KCNEI and forms a channel complex constituting the slow delayed rectifier current I-Ks. Expression of KCNQI and KCNEI are regionally heterogeneous and changes with pathological states of the heart. The aims of this study were to decipher the molecular mechanisms for transcriptional and post-transcriptional regulation expression of KCNQI and KCNEI genes and to shed light on the molecular mechanisms for their spatial heterogeneity of distribution. We cloned the 5'-flanking region and identified the transcription start sites of the KCNQI gene. We characterized the core promoters of KCNQI and KCNEI and revealed the stimulating protein (Sp 1) as a common transactivator of KCNQI and KCNEI by interacting with the Sp I cis-acting elements in the core promoter regions of these genes. We also characterized the 3' untranslated regions (3'UTRs) of the genes and experimentally established KCNQI and KCNEI as targets for repression by the muscle-specific microRNAs miR-133 and miR-1, respectively. We demonstrated spatial heterogeneity of KCNQI and KCNEI distributions at three axes (interventricular, transmural and apical-basal) and disparity between mRNA and protein expressions of these genes. We also found characteristic regional differences of expressions of SpI and miR-l/miR- 133 in the heart. Our study unraveled a novel aspect of the cellular function of miRNAs and suggests that the I-Ks-encoding genes KCNQI and KCNEI expressions are dynamically balanced by transcription factor regulation and miRNA repression. The heterogeneities of SpI and miR-I/miR-133 offer an explanation for the well-recognized regional differences and disparity between mRNA and protein expressions of KCNQI and KCNEI.