FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin a-mediated manner
FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin a-mediated manner
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DOI：
10.1128/mcb.25.4.1415-1424.2005
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发表时间：
2005-02-01
影响因子：
5.3
通讯作者：
Walter, MA
中科院分区：
文献类型：
--
作者：
Berry, FB;O'Neill, MA;Walter, MA
Foxfeld-Rieger综合征是一种常染色体显性遗传性疾病，以眼部和非眼部表型谱为特征，导致青光眼易感性增加。在人非色素睫状体上皮细胞中发现了与FOXC1相互作用的蛋白质。在这里，我们证明了FOXC1与肌动蛋白结合蛋白细丝A(Flna)相互作用。在核Flna水平升高的A7黑色素瘤细胞中，FOXC1无法激活转录，并被分割到细胞核的HP1pha异染色质富集区。这种抑制是通过FOXC1和同源结构域蛋白PBX1pha之间的相互作用而介导的。此外，我们还证明了Pbx1的有效核和亚核定位是由Flna介导的。综上所述，这些数据揭示了一种机制，即结构蛋白(如Flna)可以影响发育和病理上重要的转录因子(如FOXC1)的活性。由于FOXC1功能丧失突变和FLNA功能获得突变引起的骨骼表型相似，FLNA对FOXC1的这种抑制活性可能参与了FLNA连锁骨骼疾病的发病机制。
FOXC1 mutations underlie Axenfeld-Rieger syndrome, an autosomal dominant disorder that is characterized by a spectrum of ocular and nonocular phenotypes and results in an increased susceptibility to glaucoma. Proteins interacting with FOXC1 were identified in human nonpigmented ciliary epithelial cells. Here we demonstrate that FOXC1 interacts with the actin-binding protein filamin A (FLNA). In A7 melanoma cells possessing elevated levels of nuclear FLNA, FOXC1 is unable to activate transcription and is partitioned to an HP1alpha, heterochromatin-rich region of the nucleus. This inhibition is mediated through an interaction between FOXC1 and the homeodomain protein PBX1alpha. In addition, we demonstrate that efficient nuclear and sub-nuclear localization of PBX1 is mediated by FLNA. Together, these data reveal a mechanism by which structural proteins such as FLNA can influence the activity of a developmentally and pathologically important transcription factor such as FOXC1. Given the resemblance of the skeletal phenotypes caused by FOXC1 loss-of-function mutations and FLNA gain-of-function mutations, this inhibitory activity of FLNA on FOXC1 may contribute to the pathogenesis of FLNA-linked skeletal disorders.