A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: Selective modulation by imatinib mesylate

Swati Bhattacharyya, W. Ishida, M. Wu, M. Wilkes, Y. Mori, Monique E Hinchcliff, E. Leof, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1285-1297
Number of pages13
JournalOncogene
Volume28
Issue number10
DOIs
StatePublished - Mar 12 2009

Fingerprint

Transforming Growth Factors
Intercellular Signaling Peptides and Proteins
Fibroblasts
Fibrosis
Phosphotransferases
Skin
Imatinib Mesylate
Bleomycin
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Oncogenes
Protein-Tyrosine Kinases
Cell Survival
Collagen
Cell Proliferation
Pharmacology

Keywords

  • Egr-1
  • Fibroblast
  • Fibrosis
  • Imatinib mesylate
  • TGF-β
  • c-Abl

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Bhattacharyya, Swati ; Ishida, W. ; Wu, M. ; Wilkes, M. ; Mori, Y. ; Hinchcliff, Monique E ; Leof, E. ; Varga, John. / A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1 : Selective modulation by imatinib mesylate. In: Oncogene. 2009 ; Vol. 28, No. 10. pp. 1285-1297.
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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.",
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A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1 : Selective modulation by imatinib mesylate. / Bhattacharyya, Swati; Ishida, W.; Wu, M.; Wilkes, M.; Mori, Y.; Hinchcliff, Monique E; Leof, E.; Varga, John.

In: Oncogene, Vol. 28, No. 10, 12.03.2009, p. 1285-1297.

Research output: Contribution to journalArticle

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, Swati

AU - Ishida, W.

AU - Wu, M.

AU - Wilkes, M.

AU - Mori, Y.

AU - Hinchcliff, Monique E

AU - Leof, E.

AU - Varga, John

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Y1 - 2009/3/12

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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.

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