Published ahead of print on January 19, 2006, doi:10.1165/rcmb.2005-0300OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 5, May 2006, 561-572 A more recent version of this article appeared on May 1, 2006
Submitted on August 3, 2005 Abnormal Smooth Muscle Cell Growth in Lymphangioleiomyomatosis (LAM): Role for Tumor Suppressor TSC2Elena A Goncharova1*,1 Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA, 2 Department of Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, KY, USA, 3 Institute of Experimental Cardiology, Russian Cardiology Research Center, Moscow, Russian Federation * To whom correspondence should be addressed. 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. Despite considerable research effort, 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 LAM patients have constitutively activated S6K1, hyperphosphorylated ribosomal protein S6, activated Erk, and increased DNA synthesis compared to normal cells from the same patients. These effects were further augmented by PDGF stimulation. Interestingly, Akt activity was unchanged in LAM cells. Importantly, 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, containing the GTPase activating protein (GAP) 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. Further, loss of either TSC2 GAP activity or disruption of the TSC1/TSC2 complex dysregulates S6K1 activation, which leads to abnormal cell proliferation associated with LAM disease.
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