Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains
Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains
复制标题
DOI：
10.1093/nar/gkh571
复制
发表时间：
2004-04-01
影响因子：
14.9
通讯作者：
van Kessel, AG
中科院分区：
文献类型：
--
作者：
Kuiper, RP;Schepens, M;van Kessel, AG
碱性螺旋-环-螺旋亮氨酸拉链转录因子MiTF/TFE（MiT）家族由四个密切相关的成员MiTF、TFE 3、TFEB和TFEC组成，它们可以以同源或异源二聚体的形式结合靶DNA。使用实时RT-PCR，我们分析了这四个成员在广泛的人体组织中的相对表达水平，发现它们的表达比例是组织依赖性的。我们发现，类似于MiTF基因，TFEB和TFEC的基因包含多个可选择的第一外显子，具有限制性和差异性组织分布。在TFEB基因中鉴定出7个5'外显子，其中3个分别在胎盘和脑中特异表达。一种新的TFEC转录物（TFEC-C）编码缺乏酸性活化结构域（AAD）的N-末端截短的TFEC同种型，并且仅在肾脏和小肠中表达。此外，我们观察到相当比例的TFEC转录本剪接蛋白编码外显子，导致转录因子亚型缺乏一个或多个功能结构域，主要是碱性区域和/或AAD。这些异构体总是与完整的转录因子共表达，并可能作为MiTF/TFE蛋白的负调控因子。我们的数据显示，多个水平的调节存在的MiTF/TFE家族的转录因子，这表明这些转录因子可能参与在不同组织中的各种细胞过程。
The MiTF/TFE (MiT) family of basic helix-loop-helix leucine zipper transcription factors is composed of four closely related members, MiTF, TFE3, TFEB and TFEC, which can bind target DNA both as homo- or heterodimers. Using real-time RT-PCR, we have analyzed the relative expression levels of the four members in a broad range of human tissues, and found that their ratio of expression is tissue-dependent. We found that, similar to the MiTF gene, the genes for TFEB and TFEC contain multiple alternative first exons with restricted and differential tissue distributions. Seven alternative 5' exons were identified in the TFEB gene, of which three displayed specific expression in placenta and brain, respectively. A novel TFEC transcript (TFEC-C) encodes an N-terminally truncated TFEC isoform lacking the acidic activation domain (AAD), and is exclusively expressed in kidney and small intestine. Furthermore, we observed that a considerable proportion of the TFEC transcripts splice out protein-coding exons, resulting in transcription factor isoforms lacking one or more functional domains, primarily the basic region and/or the AAD. These isoforms were always co-expressed with the intact transcription factors and may act as negative regulators of MiTF/TFE proteins. Our data reveal that multiple levels of regulation exist for the MiTF/TFE family of transcription factors, which indicates how these transcription factors may participate in various cellular processes in different tissues.