Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts

He, S., Liu, X., Yang, Y., Huang, W., Xu, S., Yang, S., Zhang, X. and Roberts, M. S. (2010) Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts. British Journal of Dermatology, 162 3: 538-546. doi:10.1111/j.1365-2133.2009.09511.x


Author He, S.
Liu, X.
Yang, Y.
Huang, W.
Xu, S.
Yang, S.
Zhang, X.
Roberts, M. S.
Title Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts
Formatted title
Mechanisms of transforming growth factor β1/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts
Journal name British Journal of Dermatology   Check publisher's open access policy
ISSN 0007-0963
1365-2133
Publication date 2010-03
Year available 2009
Sub-type Article (original research)
DOI 10.1111/j.1365-2133.2009.09511.x
Volume 162
Issue 3
Start page 538
End page 546
Total pages 9
Editor J. English
Place of publication London, U.K
Publisher Wiley-Blackwell Publishing
Collection year 2010
Language eng
Subject C1
920117 Skin and Related Disorders
0601 Biochemistry and Cell Biology
Formatted abstract
Background:  Keloids are recognized as benign tumours characterized by fibroblastic proliferation and accumulation of extracellular matrix, especially collagen deposition. The transforming growth factor (TGF)-β1/Smad pathway plays an important role in keloid pathogenesis; however the underlying mechanisms are not fully understood.

Objectives:  To define further the mechanisms of TGF-β1/Smad signal transduction mediated by mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathways, in keloid fibroblasts.

Methods:  In the absence or presence of three MAPK (ERK, JNK and p38)-specific inhibitors, keloid fibroblasts were stimulated with exogenous TGF-β1 to activate Smad signalling. Smad protein expression was measured by immunoprecipitation/immunoblotting and immunofluorescence; plasminogen activator inhibitor (PAI)-1 transcriptional activity was measured by real-time reverse transcriptase-polymerase chain reaction analysis.

Results:  TGF-β1 induced Smad2/3 phosphorylation at both the C-terminal and the linker region, thus promoting formation of the Smad2/3/4 complex and nuclear translocation, and PAI-1 mRNA expression in keloid fibroblasts; in addition, TGF-β1 decreased inhibitory Smad7 expression. Meanwhile, the p38 inhibitor significantly inhibited Smad2/3 phosphorylation, especially at the linker region, and furthermore blocked Smad2/3/4 complex formation, and thus decreased PAI-1 mRNA expression; decreased Smad7 expression induced by TGF-β1 was also reversed by the p38 inhibitor. The ERK and JNK inhibitors interrupted Smad2/3/4 complex translocation into the nucleus and consequently decreased PAI-1 mRNA expression.

Conclusions:  These results suggested that the ERK, JNK and p38 pathways mediate TGF-β1/Smad signal transduction and might be considered as specific targets of drug therapy for keloids.
© 2009 The Authors
Keyword Keloid fibroblasts
Mitogen-activated protein kinase
Plasminogen activator inhibitor 1
Smad
TGF-beta(1)
TGF-β1
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Unknown
Additional Notes Article first published online: 22 SEP 2009. Author prepint title: "Mechanisms of MAPK pathway mediating TGF-beta(1)/Smad signal in keloid fibroblasts".

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Sun, 28 Feb 2010, 00:05:46 EST