| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 12, 10292-10297, March 22, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Departments of Mutations in the FOXC1 gene result in
Axenfeld-Rieger malformations of the anterior segment of the eye and
lead to an increased susceptibility of glaucoma. To understand how the
FOXC1 protein may function in contributing to these malformations, we
identified functional regions in FOXC1 required for nuclear
localization and transcriptional regulation. Two regions in the FOXC1
forkhead domain, one rich in basic amino acid residues, and a second,
highly conserved among all FOX proteins, were necessary for nuclear
localization of the FOXC1 protein. However, only the basic region was
sufficient for nuclear localization. Two transcriptional activation
domains were identified in the extreme N- and C-terminal regions of
FOXC1. A transcription inhibitory domain was located at the central
region of the protein. This region was able to reduce the
trans-activation potential of the C-terminal activation
domain, as well as the GAL4 activation domain. Lastly, we demonstrate
that FOXC1 is a phosphoprotein, and a number of residues predicted to
be phosphorylated were localized to the FOXC1 inhibitory domain.
Removal of residues 215-366 resulted in a transcriptionally
hyperactive FOXC1 protein, which displayed a reduced level of
phosphorylation. These results indicate that FOXC1 is under complex
regulatory control with multiple functional domains modulating FOXC1
transcriptional regulation.
FOXC1 Transcriptional Regulation Is Mediated by N- and
C-terminal Activation Domains and Contains a Phosphorylated
Transcriptional Inhibitory Domain*
§,
, and¶**
Ophthalmology and
¶ Medical Genetics, University of Alberta, Edmonton, Alberta
T6G 2H7, Canada
*
This work was supported in part by the Canadian Institutes
for Health Research (CIHR).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by an Alberta Heritage Foundation of Medical
Research (AHFMR) studentship.
**
An AHFMR Senior Scholar and a CIHR Investigator.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Beysen, L. Moumne, R. Veitia, H. Peters, B. P. Leroy, A. De Paepe, and E. De Baere Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation Hum. Mol. Genet., July 1, 2008; 17(13): 2030 - 2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Berry, J. M. Skarie, F. Mirzayans, Y. Fortin, T. J. Hudson, V. Raymond, B. A. Link, and M. A. Walter FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A Hum. Mol. Genet., February 14, 2008; 17(4): 490 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. A. Ito, T. K. Footz, T. C. Murphy, W. Courtens, and M. A. Walter Analyses of a Novel L130F Missense Mutation in FOXC1 Arch Ophthalmol, January 1, 2007; 125(1): 128 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Vernes, J. Nicod, F. M. Elahi, J. A. Coventry, N. Kenny, A.-M. Coupe, L. E. Bird, K. E. Davies, and S. E. Fisher Functional genetic analysis of mutations implicated in a human speech and language disorder Hum. Mol. Genet., November 1, 2006; 15(21): 3154 - 3167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. B. Berry, F. Mirzayans, and M. A. Walter Regulation of FOXC1 Stability and Transcriptional Activity by an Epidermal Growth Factor-activated Mitogen-activated Protein Kinase Signaling Cascade J. Biol. Chem., April 14, 2006; 281(15): 10098 - 10104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Berry, M. A. Lines, J. M. Oas, T. Footz, D. A. Underhill, P. J. Gage, and M. A. Walter Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis Hum. Mol. Genet., March 15, 2006; 15(6): 905 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Berry, Y. Tamimi, M. V. Carle, O. J. Lehmann, and M. A. Walter 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., September 15, 2005; 14(18): 2619 - 2627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. B. Berry, M. A. O'Neill, M. Coca-Prados, and M. A. Walter FOXC1 Transcriptional Regulatory Activity Is Impaired by PBX1 in a Filamin A-Mediated Manner Mol. Cell. Biol., February 15, 2005; 25(4): 1415 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Saleem, S. Banerjee-Basu, T. C. Murphy, A. Baxevanis, and M. A. Walter Essential structural and functional determinants within the forkhead domain of FOXC1 Nucleic Acids Res., August 6, 2004; 32(14): 4182 - 4193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Murphy, R. A. Saleem, T. Footz, R. Ritch, B. McGillivray, and M. A. Walter The Wing 2 Region of the FOXC1 Forkhead Domain Is Necessary for Normal DNA-Binding and Transactivation Functions Invest. Ophthalmol. Vis. Sci., August 1, 2004; 45(8): 2531 - 2538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Saleem, S. Banerjee-Basu, F. B. Berry, A. D. Baxevanis, and M. A. Walter Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1 Hum. Mol. Genet., November 15, 2003; 12(22): 2993 - 3005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Saleem, T. C. Murphy, J. M. Liebmann, and M. A. Walter Identification and Analysis of a Novel Mutation in the FOXC1 Forkhead Domain Invest. Ophthalmol. Vis. Sci., November 1, 2003; 44(11): 4608 - 4612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. Lehmann, S. Tuft, G. Brice, R. Smith, A. Blixt, R. Bell, B. Johansson, T. Jordan, R. A. Hitchings, P. T. Khaw, et al. Novel Anterior Segment Phenotypes Resulting from Forkhead Gene Alterations: Evidence for Cross-Species Conservation of Function Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2627 - 2633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Walter PITs and FOXes in Ocular Genetics The Cogan Lecture Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1402 - 1405. [Full Text] [PDF]
|
|
|
|
|
|
M. A. Lines, K. Kozlowski, and M. A. Walter Molecular genetics of Axenfeld-Rieger malformations Hum. Mol. Genet., May 15, 2002; 11(10): 1177 - 1187. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
