FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain
FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain
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DOI：
10.1074/jbc.m110266200
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发表时间：
2002-03-22
影响因子：
4.8
通讯作者：
Walter, MA
中科院分区：
文献类型：
--
作者：
Berry, FB;Saleem, RA;Walter, MA
FOXC 1基因突变导致眼前段的Axenovir-Rieger畸形，并导致青光眼易感性增加。为了了解FOXC 1蛋白如何在导致这些畸形中发挥作用，我们确定了FOXC 1中核定位和转录调节所需的功能区域。FOXC 1叉头结构域中的两个区域，一个富含碱性氨基酸残基，第二个在所有FOX蛋白中高度保守，是FOXC 1蛋白的核定位所必需的。然而，只有基本区域才足以进行核定位。两个转录激活域被确定在极端的N-和C-末端区域的FOXC 1。转录抑制结构域位于蛋白质的中心区域。该区域能够降低C-末端激活结构域以及GAL 4激活结构域的反式激活潜力。最后，我们证明，FOXC 1是一个磷蛋白，和一些残基预测被磷酸化定位到FOXC 1抑制结构域。去除残基215366导致转录活性过高的FOXC 1蛋白，其显示磷酸化水平降低。这些结果表明，FOXC 1是在复杂的监管控制与多个功能域调制FOXC 1转录调控。
Mutations in the FOXC1 gene result in Axenfeld-Rieger malformations of the anterior segment of the eye and lead to an increased susceptibility of glaucoma. To understand how the FOXC1 protein may function in contributing to these malformations, we identified functional regions in FOXC1 required for nuclear localization and transcriptional regulation. Two regions in the FOXC1 forkhead domain, one rich in basic amino acid residues, and a second, highly conserved among all FOX proteins, were necessary for nuclear localization of the FOXC1 protein. However, only the basic region was sufficient for nuclear localization. Two transcriptional activation domains were identified in the extreme N- and C-terminal regions of FOXC1. A transcription inhibitory domain was located at the central region of the protein. This region was able to reduce the trans-activation potential of the C-terminal activation domain, as well as the GAL4 activation domain. Lastly, we demonstrate that FOXC1 is a phosphoprotein, and a number of residues predicted to be phosphorylated were localized to the FOXC1 inhibitory domain. Removal of residues 215366 resulted in a transcriptionally hyperactive FOXC1 protein, which displayed a reduced level of phosphorylation. These results indicate that FOXC1 is under complex regulatory control with multiple functional domains modulating FOXC1 transcriptional regulation.