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J. Biol. Chem., Vol. 283, Issue 15, 10198-10207, April 11, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/15/10198    most recent M800624200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deng, H. Articles by Bentley, J. K. Search for Related Content PubMed PubMed Citation Articles by Deng, H. Articles by Bentley, J. K. Social Bookmarking                      What's this?

Inhibition of Glycogen Synthase Kinase-3β Is Sufficient for Airway Smooth Muscle Hypertrophy^*

Huan Deng, Gregoriy A. Dokshin, Jing Lei, Adam M. Goldsmith, Khalil N. Bitar, Diane C. Fingar, Marc B. Hershenson^¶1, and J. Kelley Bentley

From the Departments of Pediatrics and Communicable Diseases, ^¶Molecular and Integrative Physiology, and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109

We examined the role of glycogen synthase kinase-3β (GSK-3β) inhibition in airway smooth muscle hypertrophy, a structural change found in patients with severe asthma. LiCl, SB216763, and specific small interfering RNA (siRNA) against GSK-3β, each of which inhibit GSK-3β activity or expression, increased human bronchial smooth muscle cell size, protein synthesis, and expression of the contractile proteins -smooth muscle actin, myosin light chain kinase, smooth muscle myosin heavy chain, and SM22. Similar results were obtained following treatment of cells with cardiotrophin (CT)-1, a member of the interleukin-6 superfamily, and transforming growth factor (TGF)-β, a proasthmatic cytokine. GSK-3β inhibition increased mRNA expression of -actin and transactivation of nuclear factors of activated T cells and serum response factor. siRNA against eukaryotic translation initiation factor 2B (eIF2B) attenuated LiCl- and SB216763-induced protein synthesis and expression of -actin and SM22, indicating that eIF2B is required for GSK-3β-mediated airway smooth muscle hypertrophy. eIF2B siRNA also blocked CT-1- but not TGF-β-induced protein synthesis. Infection of human bronchial smooth muscle cells with pMSCV GSK-3β-A9, a retroviral vector encoding a constitutively active, nonphosphorylatable GSK-3β, blocked protein synthesis and -actin expression induced by LiCl, SB216763, and CT-1 but not TGF-β. Finally, lungs from ovalbumin-sensitized and -challenged mice demonstrated increased -actin and CT-1 mRNA expression, and airway myocytes isolated from ovalbumin-treated mice showed increased cell size and GSK-3β phosphorylation. These data suggest that inhibition of the GSK-3β/eIF2B translational control pathway contributes to airway smooth muscle hypertrophy in vitro and in vivo. On the other hand, TGF-β-induced hypertrophy does not depend on GSK-3β/eIF2B signaling.

Received for publication, January 24, 2008

^* This work was supported by National Institutes of Health Grant HL79339. 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.

¹ To whom correspondence should be addressed: 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5688. Tel.: 734-936-4200; Fax: 734-764-3200; E-mail: mhershen{at}umich.edu.

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				J. K. Bentley, H. Deng, M. J. Linn, J. Lei, G. A. Dokshin, D. C. Fingar, K. N. Bitar, W. R. Henderson Jr., and M. B. Hershenson Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3{beta} phosphorylation in a mouse model of asthma Am J Physiol Lung Cell Mol Physiol, February 1, 2009; 296(2): L176 - L184. [Abstract] [Full Text] [PDF]