title: Regulation of c-Maf and αA-Crystallin in Ocular Lens by Fibroblast Growth Factor Signaling.
abstract: Fibroblast growth factor (FGF) signaling regulates a multitude of cellular processes, including cell proliferation, survival, migration, and differentiation. In the vertebrate lens, FGF signaling regulates fiber cell differentiation characterized by high expression of crystallin proteins. However, a direct link between FGF signaling and crystallin gene transcriptional machinery remains to be established. Previously, we have shown that the bZIP proto-oncogene c-Maf regulates expression of αA-crystallin (Cryaa) through binding to its promoter and distal enhancer, DCR1, both activated by FGF2 in cell culture. Herein, we identified and characterized a novel FGF2-responsive region in the c-Maf promoter (-272/-70, FRE). Both c-Maf and Cryaa regulatory regions contain arrays of AP-1 and Ets-binding sites. Chromatin immunoprecipitation (ChIP) assays established binding of c-Jun (an AP-1 factor) and Etv5/ERM (an Ets factor) to these regions in lens chromatin. Analysis of temporal and spatial expression of c-Jun, phospho-c-Jun, and Etv5/ERM in wild type and ERK1/2 deficient lenses supports their roles as nuclear effectors of FGF signaling in mouse embryonic lens. Collectively, these studies show that FGF signaling up-regulates expression of αA-crystallin both directly and indirectly via up-regulation of c-Maf. These molecular mechanisms are applicable for other crystallins and genes highly expressed in terminally differentiated lens fibers.
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McGreal
authors.affiliation: Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Raven
authors.initials: R
authors.lastname: Harris
authors.affiliation: Laboratory of Molecular and Developmental Biology, National Eye Institute, Bethesda, Maryland 20892.
authors.forename: Chun Y
authors.initials: CY
authors.lastname: Gao
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Mason Eye Institute, University of Missouri, Columbia, Missouri 65212, and.
authors.forename: Lixing W
authors.initials: LW
authors.lastname: Reneker
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health Science University, Portland, Oregon 97239.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Musil
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, ales.cvekl@einstein.yu.edu.
authors.forename: Ales
authors.initials: A
authors.lastname: Cvekl
mesh_terms: D000818:Animals; D002642:Chick Embryo; D003459:Crystallins / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007908:Lens, Crystalline / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D061986:MCF-7 Cells; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D051257:Proto-Oncogene Proteins c-maf / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: C511246:CRYAA protein, human; D003459:Crystallins; C495607:MAF protein, human; C000715470:MAS1 protein, human; C495608:Maf protein, mouse; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D051257:Proto-Oncogene Proteins c-maf; D016222:Fibroblast Growth Factor 2; C535150:MAPK1 protein, human; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: FGF signaling; c-Maf; crystallin; differentiation; fibroblast growth factor (FGF); lens; signaling; αA-crystallin