title: Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy.
abstract: Fibrosis is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as obesity and aging. The pathogenesis of fibrosis involves multiple cell types and extracellular signals, of which transforming growth factor-ß (TGF-ß) is pre-eminent. The prevalence of fibrosis is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor Egr-1 in the pathogenesis of fibrosis. Egr-1 couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to injury and stress. In contrast to other ligand-activated transcription factors such as NF-κB, c-jun and Smad2/3 that undergo post-translational modification such as phosphorylation and nuclear translocation, Egr-1 activity is regulated via its biosynthesis. Aberrant Egr-1 expression or activity is implicated in cancer, inflammation, atherosclerosis, and ischemic injury and recent studies now indicate an important role for Egr-1 in TGF-ß-dependent profibrotic responses. Fibrosis in various animal models and human diseases such as scleroderma (SSc) and idiopathic pulmonary fibrosis (IPF) is accompanied by aberrant Egr-1 expression. Moreover Egr-1 appears to be required for physiologic and pathological connective tissue remodeling, and Egr-1-null mice are protected from fibrosis. As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.forename: Warren
authors.initials: W
authors.lastname: Tourtellotte
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000818:Animals; D003238:Connective Tissue / Q000503:physiopathology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D050880:p300-CBP Transcription Factors
chemical_list: D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; C491000:NAB2 protein, human; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors; D016315:Proto-Oncogene Proteins c-abl