TY - JOUR
T1 - A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1
T2 - Selective modulation by imatinib mesylate
AU - Bhattacharyya, S.
AU - Ishida, W.
AU - Wu, M.
AU - Wilkes, M.
AU - Mori, Y.
AU - Hinchcliff, M.
AU - Leof, E.
AU - Varga, J.
N1 - Funding Information:
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).
PY - 2009/3/12
Y1 - 2009/3/12
N2 - 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.
AB - 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.
KW - Egr-1
KW - Fibroblast
KW - Fibrosis
KW - Imatinib mesylate
KW - TGF-β
KW - c-Abl
UR - http://www.scopus.com/inward/record.url?scp=62249183044&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62249183044&partnerID=8YFLogxK
U2 - 10.1038/onc.2008.479
DO - 10.1038/onc.2008.479
M3 - Article
C2 - 19151753
AN - SCOPUS:62249183044
SN - 0950-9232
VL - 28
SP - 1285
EP - 1297
JO - Oncogene
JF - Oncogene
IS - 10
ER -