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-β (TGF-β), 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-β stimulation. Responsiveness of these MEFs to TGF-β 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-β 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-β 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-β-dependent fibrotic processes.
Original language | English (US) |
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Pages (from-to) | 1285-1297 |
Number of pages | 13 |
Journal | Oncogene |
Volume | 28 |
Issue number | 10 |
DOIs | |
State | Published - Mar 12 2009 |
Funding
We are grateful to Anthony Koleske (Yale University, New Haven, CT, USA) and Pamela Woodring (The Salk Institute, La Jolla, CA) for Abl-null/Arg-null and Abl reconstituted mouse embryonic fibroblasts, and Leonidas Platanias (North-western University Feinberg School of Medicine) for Bcr-Abl plasmids and helpful discussions. This study was supported by grants from the National Institutes of Health (AR-42309) and the Department of Defence (W81-XWH-06-01-0278).
Keywords
- Egr-1
- Fibroblast
- Fibrosis
- Imatinib mesylate
- TGF-β
- c-Abl
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Cancer Research