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: Swati Bhattacharyya, Minghua Wu, Feng Fang, Warren Tourtellotte, Carol Feghali-Bostwick, John Varga
• Journal: Matrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 30 Issue 4 Pg. 235-42 (May 2011) ISSN: 1569-1802 [Electronic] Netherlands
• PMID: 21511034 (Publication Type: Journal Article, Review)
• Copyright: Published by Elsevier B.V.

Chemical References

• Early Growth Response Protein 1
• Early Growth Response Transcription Factors
• NAB2 protein, human
• Repressor Proteins
• Transforming Growth Factor beta
• p300-CBP Transcription Factors
• Proto-Oncogene Proteins c-abl

Topics

• Animals
• Connective Tissue (physiopathology)
• Early Growth Response Protein 1 (genetics, metabolism)
• Early Growth Response Transcription Factors (genetics, metabolism)
• Fibroblasts (metabolism)
• Fibrosis (drug therapy, metabolism)
• Homeostasis
• Humans
• Proto-Oncogene Proteins c-abl (metabolism)
• Repressor Proteins (metabolism)
• Scleroderma, Systemic (drug therapy, metabolism)
• Transcription, Genetic
• Transforming Growth Factor beta (metabolism)
• p300-CBP Transcription Factors