Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional Repressors
Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional Repressors
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DOI：
10.1074/jbc.m207174200
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发表时间：
2003-07-04
影响因子：
4.8
通讯作者：
Tucker, P
中科院分区：
文献类型：
--
作者：
Wang, B;Lin, DJ;Tucker, P
叉头/HNF 3转录因子的Foxp亚家族最近已被确认，因为其参与自身免疫性疾病、言语和语言障碍以及肺发育。这个亚家族的独特结构域包括一个发散的DNA结合翼螺旋，一个亮氨酸拉链，一个锌指和一个多聚谷氨酰胺束。很少有人知道这些蛋白质的性质，是根本的，他们的功能作为转录因子，也没有Foxp序列基序如何调节其转录调控特性。我们在这里报告的Foxp 1蛋白的结构/功能分析。我们分析了选择性剪接异构体1A和1C，并报告了一种新的异构体Foxp 1D，缺乏多聚谷氨酰胺结构域的克隆和表征。我们已经分离出Foxp 1转录因子的首选DNA结合位点。Foxp 1A、Foxp 1C和Foxp 1D同种型以及相关Foxp 2蛋白通过与该共有位点或与SV 40和白细胞介素-2启动子内的天然存在位点结合来抑制基因转录。在某些情况下，Foxp 1抑制的强度由多聚谷氨酰胺结构域介导。与以前的特征叉头因子，Foxp 1蛋白可以形成同源二聚体或异源二聚体与亚家族成员。二聚化结构域定位于进化上保守的C2 H2锌指和亮氨酸拉链基序。最后，我们证明，Foxp 1，虽然广泛表达，进一步调节这些功能重要的序列结构域的组织特异性选择性剪接。这些结果表明Foxp 1蛋白在不同的细胞和组织类型中具有不同的功能作用。
The Foxp subfamily of forkhead/HNF3 transcription factors has recently been recognized because of its involvement in autoimmune disease, speech and language disorders, and lung development. Domains unique to this subfamily include a divergent DNA-binding winged helix, a leucine zipper, a zinc finger, and a polyglutamine tract. Little is known about the properties of these proteins that are fundamental to their function as transcription factors nor how the Foxp sequence motifs regulate their transcriptional regulatory properties. We report here a structure/function analysis of the Foxp1 protein. We have analyzed the alternative splice isoforms 1A and 1C and also report the cloning and characterization of a novel isoform Foxp1D that lacks the polyglutamine domain. We have isolated the preferred DNA-binding sites for Foxp1 transcription factors. Foxp1A, C, and D isoforms and the related Foxp2 protein repress gene transcription via binding to this consensus site or to a naturally occurring site within the SV40 and the interleukin-2 promoters. In some cases the strength of Foxp1 repression is mediated by the polyglutamine domain. Unlike previously characterized forkhead factors, Foxp1 proteins can form homodimers or heterodimers with subfamily members. The dimerization domain was localized to an evolutionarily conserved C2H2 zinc finger and leucine zipper motif. Finally, we demonstrate that Foxp1, although broadly expressed, is further regulated by tissue-specific alternative splicing of these functionally important sequence domains. These results suggest that Foxp1 proteins have diverse functional roles in different cell and tissue types.