title: A non-Smad mechanism of fibroblast activation by transforming growth factor-beta via c-Abl and Egr-1: selective modulation by imatinib mesylate.
abstract: The nonreceptor protein tyrosine kinase c-Abl regulates cell proliferation and survival. Recent studies provide evidence that implicate c-Abl as a mediator for fibrotic responses induced by transforming growth factor-beta (TGF-beta), but the precise mechanisms underlying this novel oncogene function are unknown. Here, we report that when expressed in normal fibroblasts, a constitutively active mutant of Abl that causes chronic myelogenous leukemia (CML) stimulated the expression and transcriptional activity of the early growth response factor 1 (Egr-1). Mouse embryonic fibroblasts (MEFs), lacking c-Abl, were resistant to TGF-beta stimulation. Responsiveness of these MEFs to TGF-beta could be rescued by wild-type c-Abl, but not by a kinase-deficient mutant form of c-Abl. Furthermore, Abl kinase activity was necessary for the induction of Egr-1 by TGF-beta in normal fibroblasts, and Egr-1 was required for stimulation of collagen by Bcr-Abl. Lesional skin fibroblasts in mice with bleomycin-induced fibrosis of skin displayed evidence of c-Abl activation in situ, and elevated phospho-c-Abl correlated with increased local expression of Egr-1. Collectively, these results position Egr-1 downstream of c-Abl in the fibrotic response, delineate a novel Egr-1-dependent intracellular signaling mechanism that underlies the involvement of c-Abl in certain TGF-beta responses, and identify Egr-1 as a target of inhibition by imatinib. Furthermore, the findings show in situ activation of c-Abl paralleling the upregulated tissue expression of Egr-1 that accompanies fibrosis. Pharmacological targeting of c-Abl and its downstream effector pathways may, therefore, represent a novel therapeutic approach to blocking TGF-beta-dependent fibrotic processes.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: W
authors.initials: W
authors.lastname: Ishida
authors.forename: M
authors.initials: M
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Wilkes
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.forename: M
authors.initials: M
authors.lastname: Hinchcliff
authors.forename: E
authors.initials: E
authors.lastname: Leof
authors.forename: J
authors.initials: J
authors.lastname: Varga
mesh_terms: D000818:Animals; D001549:Benzamides; D001761:Bleomycin / Q000633:toxicity; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D005355:Fibrosis; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D000068877:Imatinib Mesylate; D003094:Collagen; D016315:Proto-Oncogene Proteins c-abl; D048049:Extracellular Signal-Regulated MAP Kinases