A non-Smad mechanism of fibroblast activation by transforming growth factor-beta via c-Abl and Egr-1: selective modulation by imatinib mesylate. Export

@article{citeulike:3914556, 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.}, author = {Bhattacharyya, S. and Ishida, W. and Wu, M. and Wilkes, M. and Mori, Y. and Hinchcliff, M. and Leof, E. and Varga, J.}, citeulike-article-id = {3914556}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/onc.2008.479}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19151753}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19151753}, day = {12}, doi = {10.1038/onc.2008.479}, issn = {1476-5594}, journal = {Oncogene}, keywords = {abl, egr, fbl, imatinib, smad-independent, tgfb}, month = {March}, number = {10}, pages = {1285--1297}, posted-at = {2009-07-31 13:26:40}, priority = {2}, publisher = {Nature Publishing Group}, title = {A non-Smad mechanism of fibroblast activation by transforming growth factor-beta via c-Abl and Egr-1: selective modulation by imatinib mesylate.}, url = {http://dx.doi.org/10.1038/onc.2008.479}, volume = {28}, year = {2009} }

TY - JOUR ID - citeulike:3914556 L3 - citeulike-article-id:3914556 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-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. IS - 10 JF - Oncogene SN - 1476-5594 EP - 1297 TI - A non-Smad mechanism of fibroblast activation by transforming growth factor-beta via c-Abl and Egr-1: selective modulation by imatinib mesylate. PB - Nature Publishing Group VL - 28 SP - 1285 KW - abl KW - egr KW - fbl KW - imatinib KW - smad-independent KW - tgfb AU - Bhattacharyya, S AU - Ishida, W AU - Wu, M AU - Wilkes, M AU - Mori, Y AU - Hinchcliff, M AU - Leof, E AU - Varga, J PY - 2009/03/12/ UR - http://dx.doi.org/10.1038/onc.2008.479 ER -