help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Published ahead of print on September 22, 2005, doi:10.1164/rccm.200507-1058OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 1, January 2006, 112-121

A more recent version of this article appeared on January 1, 2006
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200507-1058OCv1
173/1/112    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 White, E. S
Right arrow Articles by Toews, G. B
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by White, E. S
Right arrow Articles by Toews, G. B

Submitted on July 8, 2005
Accepted on September 20, 2005

Negative Regulation of Myofibroblast Differentiation by PTEN

Eric S White1*, Rachelle G Atrasz1, Biao Hu2, Sem H Phan2, Vuk Stambolic3, Tak W Mak3, Cory M Hogaboam2, Kevin R Flaherty1, Fernando J Martinez1, Christopher D Kontos4, and Galen B Toews1

1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, USA, 2 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA, 3 University of Toronto, University Health Network, Ontario Cancer Institute, Toronto, Ontario, Canada, 4 Division of Cardiology, Duke University Medical Center, Durham, NC, USA

* To whom correspondence should be addressed. E-mail: docew{at}umich.edu.

Rationale: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis. Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. Objective: To show that myofibroblast differentiation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity in vivo and to identify a potential mechanism by which this occurs. Methods: We utilized tissue sections of surgical lung biopsies from patients with idiopathic pulmonary fibrosis to localize expression of PTEN and {alpha}-SMA. We utilized cell culture of pten-/- and wild-type fibroblasts as well as adenoviral strategies and pharmacologic inhibitors to determine the mechanism by which PTEN inhibits {alpha}-SMA, fibroblast proliferation, and collagen production. Results: In human lung specimens of idiopathic pulmonary fibrosis, myofibroblasts within fibroblastic foci demonstrate diminished PTEN expression. Further, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten-/- fibroblasts, and in normal fibroblasts in which PTEN is inhibited, {alpha}-SMA, proliferation, and collagen production is upregulated. Addition of transforming growth factor-{beta} to wild-type cells, but not pten-/- cells, results in increased {alpha}-SMA expression in a time-dependent fashion. In pten-/- cells, reconstitution of PTEN decreases {alpha}-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibits transforming growth factor-{beta}-induced myofibroblast differentiation. Both the protein and lipid phosphatase actions of PTEN are capable of modulating the myofibroblast phenotype. Conclusions: The results indicate that in idiopathic pulmonary fibrosis, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.
Key words: myofibroblast; fibrosis; PTEN; phosphatase; smooth muscle actin




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
R. L. Sagana, M. Yan, A. M. Cornett, J. L. Tsui, D. A. Stephenson, S. K. Huang, B. B. Moore, M. N. Ballinger, J. Melonakos, C. D. Kontos, et al.
Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) Directs Prostaglandin E2-mediated Fibroblast Responses via Regulation of E Prostanoid 2 Receptor Expression
J. Biol. Chem., November 20, 2009; 284(47): 32264 - 32271.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
A. K. Ghosh, S. Bhattacharyya, J. Wei, S. Kim, Y. Barak, Y. Mori, and J. Varga
Peroxisome proliferator-activated receptor-{gamma} abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator
FASEB J, September 1, 2009; 23(9): 2968 - 2977.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
W. D. Hardie, S. W. Glasser, and J. S. Hagood
Emerging Concepts in the Pathogenesis of Lung Fibrosis
Am. J. Pathol., July 1, 2009; 175(1): 3 - 16.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. Wu, D. S. Melichian, E. Chang, M. Warner-Blankenship, A. K. Ghosh, and J. Varga
Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-{gamma}
Am. J. Pathol., February 1, 2009; 174(2): 519 - 533.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
K. Vaahtomeri, E. Ventela, K. Laajanen, P. Katajisto, P.-J. Wipff, B. Hinz, T. Vallenius, M. Tiainen, and T. P. Makela
Lkb1 is required for TGF{beta}-mediated myofibroblast differentiation
J. Cell Sci., November 1, 2008; 121(21): 3531 - 3540.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Bu, B. Kapanadze, T. Hsu, and M. Trojanowska
Opposite Effects of Dihydrosphingosine 1-Phosphate and Sphingosine 1-Phosphate on Transforming Growth Factor-{beta}/Smad Signaling Are Mediated through the PTEN/PPM1A-dependent Pathway
J. Biol. Chem., July 11, 2008; 283(28): 19593 - 19602.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
H. Xia, D. Diebold, R. Nho, D. Perlman, J. Kleidon, J. Kahm, S. Avdulov, M. Peterson, J. Nerva, P. Bitterman, et al.
Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis
J. Exp. Med., July 7, 2008; 205(7): 1659 - 1672.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
A. F. Muro, F. A. Moretti, B. B. Moore, M. Yan, R. G. Atrasz, C. A. Wilke, K. R. Flaherty, F. J. Martinez, J. L. Tsui, D. Sheppard, et al.
An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis
Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 638 - 645.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
B. E.J. Teunissen, P. J.H. Smeets, P. H.M. Willemsen, L. J. De Windt, G. J. Van der Vusse, and M. Van Bilsen
Activation of PPAR{delta} inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts
Cardiovasc Res, August 1, 2007; 75(3): 519 - 529.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
E. M. Pierce, K. Carpenter, C. Jakubzick, S. L. Kunkel, H. Evanoff, K. R. Flaherty, F. J. Martinez, G. B. Toews, and C. M. Hogaboam
Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21
Eur. Respir. J., June 1, 2007; 29(6): 1082 - 1093.
[Abstract] [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 page
 Am. J. Respir. Crit. Care Med.Home page
A. U. Wells and C. M. Hogaboam
Update in Diffuse Parenchymal Lung Disease 2006
Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 655 - 660.
[Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
E. M. Pierce, K. Carpenter, C. Jakubzick, S. L. Kunkel, K. R. Flaherty, F. J. Martinez, and C. M. Hogaboam
Therapeutic Targeting of CC Ligand 21 or CC Chemokine Receptor 7 Abrogates Pulmonary Fibrosis Induced by the Adoptive Transfer of Human Pulmonary Fibroblasts to Immunodeficient Mice
Am. J. Pathol., April 1, 2007; 170(4): 1152 - 1164.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
K. Kuwano
PTEN as a New Agent in the Fight against Fibrogenesis
Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 5 - 6.
[Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2005 American Thoracic Society 		  2nd Annual Dinner