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Published ahead of print on April 22, 2004, doi:10.1165/rcmb.2003-0272OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 3, September 2004, 266-275

A more recent version of this article appeared on September 1, 2004
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Submitted on July 23, 2003
Revised on April 22, 2004

PI(3)Kinase/mTOR/p70S6K Regulates Contractile Protein Accumulation in Airway Myocyte Differentiation

Andrew J Halayko1*, Sreedharan Kartha2, Gerald L Stelmack1, John McConville2, John Tam1, Blanca Camoretti-Mercado2, Sean M Forsythe2, Marc B Hershenson3, and Julian Solway2

1 Department of Physiology, and Section of Respiratory Diseases, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada, 2 Departments of Medicine and Pediatrics, University of Chicago, Chicago, IL, USA, 3 Departments of Pediatrics and Communicable Diseases, Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

* To whom correspondence should be addressed. E-mail: ahalayk{at}cc.umanitoba.ca.

Increased airway smooth muscle in airway remodeling results from myocyte proliferation and hypertrophy. Skeletal and vascular smooth muscle hypertrophy is induced by phosphatidylinositide-3 kinase (PI(3) kinase) via mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K). We tested the hypothesis that this pathway regulates contractile protein accumulation in cultured canine airway myocytes acquiring an elongated contractile phenotype in serum-free culture. In vitro assays revealed a sustained activation of PI(3) kinase and p70S6K during serum deprivation up to 12 days, with concomitant accumulation of SM22 and smooth muscle myosin heavy chain (smMHC) proteins. Immunocytochemistry revealed that activation of PI3K/mTOR/p70S6K occurred almost exclusively in myocytes that acquire the contractile phenotype. Inhibition of PI(3) kinase or mTOR with LY294002 or rapamycin blocked p70S6K activation, prevented formation of large elongated contractile phenotype myocytes, and blocked accumulation of SM22 and smMHC. Inhibition of MEK had no effect. Steady state mRNA abundance for SM22 and smMHC was unaffected by blocking p70S6K activation. These studies provide primary evidence that PI(3) kinase and mTOR activate p70S6K in airway myocytes, which in turn is required for accumulation of contractile apparatus proteins, differentiation, and growth of large, elongated contractile phenotype airway smooth muscle cells.




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