This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Berry, F. B. Articles by Walter, M. A. Search for Related Content PubMed PubMed Citation Articles by Berry, F. B. Articles by Walter, M. A.

 Previous Article  |  Next Article 

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

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, 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.

This article has been cited by other articles:

• Corry, G. N., Hendzel, M. J., Underhill, D. A. (2008). Subnuclear localization and mobility are key indicators of PAX3 dysfunction in Waardenburg syndrome. Hum Mol Genet 17: 1825-1837 [Abstract] [Full Text]  
• Oppenheimer, O., Cheung, N.-K., Gerald, W. L. (2007). The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Molecular Cancer Therapeutics 6: 1300-1309 [Abstract] [Full Text]  
• Hart, A. W., Morgan, J. E., Schneider, J., West, K., McKie, L., Bhattacharya, S., Jackson, I. J., Cross, S. H. (2006). Cardiac malformations and midline skeletal defects in mice lacking filamin A. Hum Mol Genet 15: 2457-2467 [Abstract] [Full Text]  
• Berry, F. B., Mirzayans, F., Walter, M. A. (2006). Regulation of FOXC1 Stability and Transcriptional Activity by an Epidermal Growth Factor-activated Mitogen-activated Protein Kinase Signaling Cascade. J. Biol. Chem. 281: 10098-10104 [Abstract] [Full Text]  
• Berry, F. B., Lines, M. A., Oas, J. M., Footz, T., Underhill, D. A., Gage, P. J., Walter, M. A. (2006). Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet 15: 905-919 [Abstract] [Full Text]  
• Berry, F. B., Tamimi, Y., Carle, M. V., Lehmann, O. J., Walter, M. A. (2005). The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Hum Mol Genet 14: 2619-2627 [Abstract] [Full Text]