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Published ahead of print on January 19, 2006, doi:10.1165/rcmb.2005-0300OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 561-572, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0300OC

Abnormal Growth of Smooth Muscle–Like Cells in Lymphangioleiomyomatosis

Role for Tumor Suppressor TSC2

Elena A. Goncharova, Dmitriy A. Goncharov, Matthew Spaits, Daniel J. Noonan, Ekaterina Talovskaya, Andrew Eszterhas and Vera P. Krymskaya

Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, Kentucky; Laboratory of Molecular Endocrinology, and Institute of Experimental Cardiology, Russian Cardiology Research Center, Moscow, Russia

Correspondence and requests for reprints should be addressed to Elena A. Goncharova, Ph.D., Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, 421 Curie Boulevard, BRB II/III, Philadelphia, PA 19104-6160. E-mail: goncharo{at}mail.med.upenn.edu

The TSC1 and TSC2 proteins, which function as a TSC1/TSC2 tumor suppressor complex, are associated with lymphangioleiomyomatosis (LAM), a genetic disorder characterized by the abnormal growth of smooth muscle–like cells in the lungs. The precise molecular mechanisms that modulate LAM cell growth remain unknown. We demonstrate that TSC2 regulates LAM cell growth. Cells dissociated from LAM nodules from the lungs of five different patients with LAM have constitutively activated S6K1, hyperphosphorylated ribosomal protein S6, activated Erk, and increased DNA synthesis compared with normal cells from the same patients. These effects were augmented by PDGF stimulation. Akt activity was unchanged in LAM cells. Rapamycin, a specific S6K1 inhibitor, abolished increased LAM cell growth. The full-length TSC2 was necessary for inhibition of S6 hyperphosphorylation and DNA synthesis in LAM cells, as demonstrated by co-microinjection of the C-terminus, which contains the GTPase activating protein homology domain, and the N-terminus, which binds TSC1. Our data demonstrate that increased LAM cell growth is associated with constitutive S6K1 activation, which is extinguishable by TSC2 expression. Loss of TSC2 GAP activity or disruption of the TSC1/TSC2 complex dysregulates S6K1 activation, which leads to abnormal cell proliferation associated with LAM disease.

Key Words: interstitial lung disease • smooth muscle • TSC




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