FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin A-mediated manner.
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.
Berry
Fred B
FB
Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada. fberry@ualberta.ca
O'Neill
Megan A
MA
Coca-Prados
Miguel
M
Walter
Michael A
MA
D002458:Cell Fractionation; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism; D064448:Filamins; D051858:Forkhead Transcription Factors; D006367:HeLa Cells; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D003285:Contractile Proteins; D004268:DNA-Binding Proteins; C112743:FOXC1 protein, human; D064448:Filamins; D051858:Forkhead Transcription Factors; D006570:Heterochromatin; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000090266:Chromobox Protein Homolog 5