1: Mol Cell Biol. 2005 Feb;25(4):1415-24. 

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

Berry FB, O'Neill MA, Coca-Prados M, Walter MA.

Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada.
fberry@ualberta.ca

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 PBX1a. In addition, we
demonstrate that efficient nuclear and subnuclear 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.

PMID: 15684392 [PubMed - indexed for MEDLINE]


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