Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS One. 2013 Apr 16;8(4):e60526. doi: 10.1371/journal.pone.0060526. Print 2013.
The C-terminus of the voltage-gated calcium channel Cav1.2 encodes a transcription factor, the calcium channel associated transcriptional regulator (CCAT), that regulates neurite extension and inhibits Cav1.2 expression. The mechanisms by which CCAT is generated in neurons and myocytes are poorly understood. Here we show that CCAT is produced by activation of a cryptic promoter in exon 46 of CACNA1C, the gene that encodes CaV1.2. Expression of CCAT is independent of Cav1.2 expression in neuroblastoma cells, in mice, and in human neurons derived from induced pluripotent stem cells (iPSCs), providing strong evidence that CCAT is not generated by cleavage of CaV1.2. Analysis of the transcriptional start sites in CACNA1C and immune-blotting for channel proteins indicate that multiple proteins are generated from the 3' end of the CACNA1C gene. This study provides new insights into the regulation of CACNA1C, and provides an example of how exonic promoters contribute to the complexity of mammalian genomes.
电压门控钙通道 Cav1.2 的 C 端编码一种转录因子，即钙通道相关转录调节剂（CCAT），它调节轴突延伸并抑制 Cav1.2 的表达。神经元和心肌细胞中 CCAT 的产生机制尚未完全清楚。本文中，我们发现 CCAT 是通过 CACNA1C 外显子 46 中的隐匿启动子激活产生的，CACNA1C 基因编码 CaV1.2。在神经母细胞瘤细胞、小鼠和诱导多能干细胞（iPSC）衍生的人类神经元中，CCAT 的表达独立于 Cav1.2 的表达，这提供了强有力的证据表明 CCAT 不是通过 CaV1.2 的切割产生的。对 CACNA1C 的转录起始位点的分析和通道蛋白的免疫印迹表明，多种蛋白是从 CACNA1C 基因的 3' 端产生的。本研究为 CACNA1C 的调控提供了新的见解，并为外显子启动子如何促进哺乳动物基因组的复杂性提供了一个范例。
