HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 10, 8873-8878, March 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/10/8873    most recent M309698200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohnishi, H. Articles by Sugano, K. Search for Related Content PubMed PubMed Citation Articles by Ohnishi, H. Articles by Sugano, K. Social Bookmarking                      What's this?

Distinct Roles of Smad2-, Smad3-, and ERK-dependent Pathways in Transforming Growth Factor-₁ Regulation of Pancreatic Stellate Cellular Functions^*

Hirohide Ohnishi, Tomohiko Miyata, Hiroshi Yasuda¶, Yukihiro Satoh, Kazunobu Hanatsuka, Hiroto Kita, Akira Ohashi, Kiichi Tamada, Noriko Makita||, Taroh Iiri||, Namiki Ueda**, Hirosato Mashima**, and Kentaro Sugano

From the Department of Gastroenterology, Jichi Medical School, Tochigi 329-0498, Japan, the ^¶Division of Gastroenterology, Showa University Fujigaoka Hospital, Kanagawa 227-8501, Japan, the ^||Department of Endocrinology and Nephrology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan, and the ^**Department of Gastroenterology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan

Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor-₁ (TGF-₁) regulates PSC activation and proliferation in an autocrine manner. The intracellular signaling pathways of the regulation were examined in this study. Immunoprecipitation and immunocytochemistry revealed that Smad2, Smad3, and Smad4 were functionally expressed in PSCs. Adenovirus-mediated expression of Smad2, Smad3, or dominant-negative Smad2/3 did not alter TGF-₁ mRNA expression level or the amount of autocrine TGF-₁ peptide. However, expression of dominant-negative Smad2/3 inhibited PSC activation and enhanced their proliferation. Co-expression of Smad2 with dominant-negative Smad2/3 restored PSC activation inhibited by dominant-negative Smad2/3 expression without changing their proliferation. By contrast, co-expression of Smad3 with dominant-negative Smad2/3 attenuated PSC proliferation enhanced by dominant-negative Smad2/3 expression without altering their activation. Exogenous TGF-₁ increased TGF₁ mRNA expression in PSCs. However, PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MEK1), inhibited ERK activation by TGF-₁, and consequently attenuated TGF-₁ enhancement of its own mRNA expression in PSCs. We propose that TGF-₁ differentially regulates PSC activation, proliferation, and TGF-₁ mRNA expression through Smad2-, Smad3-, and ERK-dependent pathways, respectively.

Received for publication, September 2, 2003 , and in revised form, December 3, 2003.

^* This work was supported by grants-in-aid from the ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Gastroenterology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachicho, Kawachi-gun, Tochigi 329-0498, Japan. E-mail: hohnishi{at}jichi.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]

				L. L. Koth, B. Alex, S. Hawgood, M. A. Nead, D. Sheppard, D. J. Erle, and D. G. Morris Integrin beta6 Mediates Phospholipid and Collectin Homeostasis by Activation of Latent TGF-beta1 Am. J. Respir. Cell Mol. Biol., December 1, 2007; 37(6): 651 - 659. [Abstract] [Full Text] [PDF]

				L. Hakkinen and A. Csiszar Hereditary Gingival Fibromatosis: Characteristics and Novel Putative Pathogenic Mechanisms J. Dent. Res., January 1, 2007; 86(1): 25 - 34. [Abstract] [Full Text] [PDF]

				H. Aoki, H. Ohnishi, K. Hama, S. Shinozaki, H. Kita, H. Osawa, H. Yamamoto, K. Sato, K. Tamada, and K. Sugano Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines Am J Physiol Cell Physiol, January 1, 2007; 292(1): C259 - C268. [Abstract] [Full Text] [PDF]

				H. Aoki, H. Ohnishi, K. Hama, T. Ishijima, Y. Satoh, K. Hanatsuka, A. Ohashi, S. Wada, T. Miyata, H. Kita, et al. Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1100 - C1108. [Abstract] [Full Text] [PDF]

				Y. Q. Xiao, C. G. Freire-de-Lima, W. J. Janssen, K. Morimoto, D. Lyu, D. L. Bratton, and P. M. Henson Oxidants Selectively Reverse TGF-{beta} Suppression of Proinflammatory Mediator Production J. Immunol., January 15, 2006; 176(2): 1209 - 1217. [Abstract] [Full Text] [PDF]

				M Pinzani Pancreatic stellate cells: new kids become mature Gut, January 1, 2006; 55(1): 12 - 14. [Full Text] [PDF]

				M. Uemura, E. S. Swenson, M. D.A. Gaca, F. J. Giordano, M. Reiss, and R. G. Wells Smad2 and Smad3 Play Different Roles in Rat Hepatic Stellate Cell Function and {alpha}-Smooth Muscle Actin Organization Mol. Biol. Cell, September 1, 2005; 16(9): 4214 - 4224. [Abstract] [Full Text] [PDF]

				B. Qiao, S. R. Padilla, and P. D. Benya Transforming Growth Factor (TGF)-{beta}-activated Kinase 1 Mimics and Mediates TGF-{beta}-induced Stimulation of Type II Collagen Synthesis in Chondrocytes Independent of Col2a1 Transcription and Smad3 Signaling J. Biol. Chem., April 29, 2005; 280(17): 17562 - 17571. [Abstract] [Full Text] [PDF]