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Molecular and Cellular Biology, February 2005, p. 1415-1424, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1415-1424.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

FOXC1 Transcriptional Regulatory Activity Is Impaired by PBX1 in a Filamin A-Mediated Manner

Fred B. Berry,1* Megan A. O'Neill,2 Miguel Coca-Prados,3 and Michael A. Walter1,2

Departments of Ophthalmology,1 Medical Genetics, University of Alberta, Edmonton, Alberta, Canada,2 Department of Ophthalmology and Visual Sciences, Yale University Medical School, New Haven, Connecticut3

Received 5 July 2004/ Returned for modification 12 August 2004/ Accepted 3 November 2004

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 HP1{alpha}, 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.

* Corresponding author. Mailing address: Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada T6G 2H7. Phone: (780) 492-3028. Fax: (780) 492-6934. Email: fberry{at}ualberta.ca.

Molecular and Cellular Biology, February 2005, p. 1415-1424, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1415-1424.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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