FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin a-mediated manner

被引:56
作者
Berry, FB [1 ]
O'Neill, MA
Coca-Prados, M
Walter, MA
机构
[1] Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2H7, Canada
[2] Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada
[3] Yale Univ, Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT 06510 USA
关键词
D O I
10.1128/MCB.25.4.1415-1424.2005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1415 / 1424
页数:10
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