help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on July 20, 2006, doi:10.1165/rcmb.2006-0043OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2006-0043OCv1
36/1/78    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hu, B.
Right arrow Articles by Phan, S. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hu, B.
Right arrow Articles by Phan, S. H.
American Journal of Respiratory Cell and Molecular Biology. Vol. 36, pp. 78-84, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0043OC

Gut-Enriched Krüppel-Like Factor Interaction with Smad3 Inhibits Myofibroblast Differentiation

Biao Hu, Zhe Wu, Tianju Liu, Matthew R. Ullenbruch, Hong Jin and Sem H. Phan

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Dr. Sem H. Phan, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602. E-mail: shphan{at}umich.edu

Gut-enriched Krüppel-like factor (GKLF) has been reported to partially inhibit {alpha}-smooth muscle actin ({alpha}-SMA) gene transcription by competing for binding to the TGF-beta control element (TCE) with known activators such as Sp1 and other Krüppel-like factors. This incomplete inhibition via the TCE suggests an additional mechanism, which was evaluated in this study. The results showed that an {alpha}-SMA promoter mutated in the TCE remained susceptible to inhibition by GKLF in rat lung fibroblasts consistent with the existence of an additional TCE-independent mechanism. Since TGF-beta– induced {alpha}-SMA expression is Smad3-dependent, potential interaction between GKLF and Smad3 was examined as a basis for this additional inhibitory mechanism. Co-immunoprecipitation and yeast two-hybrid assays revealed that GKLF could bind Smad3 through the Smad3 MH2 domain. Electrophoretic mobility shift assays and ChIP assay indicated that this GKLF–Smad3 interaction inhibited Smad3 binding to the Smad3-binding element (SBE) in the {alpha}-SMA promoter, and the activity of an SBE containing artificial promoter. Further analysis using smad3(–/–) fibroblasts confirmed that the TCE-independent inhibition by GKLF was dependent on Smad3. These data taken together suggest that in addition to inhibition via the TCE, GKLF represses {alpha}-SMA gene expression by interacting with Smad3 to prevent Smad3 binding to the SBE. It represents the first evidence to directly link GKLF with Smad3, a key intracellular mediator of TGF-beta signaling, which should lead to a clearer understanding of the mechanism of how GKLF regulates TGF-beta–induced gene expression.

Key Words: {alpha}-smooth muscle actin • GKLF • KLF4 • Smad3 • TGF-beta


CLINICAL RELEVANCE

Our data taken together suggest that in addition to inhibition via the TCE, GKLF represses {alpha}-SMA gene expression by interacting with Smad3 to prevent Smad3 binding to the SBE. It represents the first evidence to directly link GKLF with Smad3.

 



This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
W. Guo, B. Shan, R. C. Klingsberg, X. Qin, and J. A. Lasky
Abrogation of TGF-{beta}1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition
Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L864 - L870.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
N. Sandbo, S. Kregel, S. Taurin, S. Bhorade, and N. O. Dulin
Critical Role of Serum Response Factor in Pulmonary Myofibroblast Differentiation Induced by TGF-{beta}
Am. J. Respir. Cell Mol. Biol., September 1, 2009; 41(3): 332 - 338.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
T. Liu, B. Hu, Y. Y. Choi, M. Chung, M. Ullenbruch, H. Yu, J. B. Lowe, and S. H. Phan
Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation
Am. J. Pathol., May 1, 2009; 174(5): 1745 - 1755.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
S. H. Phan
Biology of Fibroblasts and Myofibroblasts
Proceedings of the ATS, April 15, 2008; 5(3): 334 - 337.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
J. S. Hagood and M. A. Olman
Muscle Fatigue: MK2 Signaling and Myofibroblast Differentiation
Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 503 - 506.
[Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
B. Hinz, S. H. Phan, V. J. Thannickal, A. Galli, M.-L. Bochaton-Piallat, and G. Gabbiani
The Myofibroblast: One Function, Multiple Origins
Am. J. Pathol., June 1, 2007; 170(6): 1807 - 1816.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2007 American Thoracic Society. 		  SOTA, FL