• Elena A Goncharova, Dmitry A Goncharov, Melane L James, Elena N Atochina-Vasserman, Victoria Stepanova, Seung-Beom Hong, Hua Li, Linda Gonzales, Masaya Baba, W Marston Linehan, Andrew J Gow, Susan Margulies, Susan Guttentag, Laura S Schmidt, and Vera P Krymskaya.
• Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
• Cell Rep. 2014 Apr 24; 7 (2): 412-423.

AbstractSpontaneous pneumothoraces due to lung cyst rupture afflict patients with the rare disease Birt-Hogg-Dubé (BHD) syndrome, which is caused by mutations of the tumor suppressor gene folliculin (FLCN). The underlying mechanism of the lung manifestations in BHD is unclear. We show that BHD lungs exhibit increased alveolar epithelial cell apoptosis and that Flcn deletion in mouse lung epithelium leads to cell apoptosis, alveolar enlargement, and an impairment of both epithelial barrier and overall lung function. We find that Flcn-null epithelial cell apoptosis is the result of impaired AMPK activation and increased cleaved caspase-3. AMPK activator LKB1 and E-cadherin are downregulated by Flcn loss and restored by its expression. Correspondingly, Flcn-null cell survival is rescued by the AMPK activator AICAR or constitutively active AMPK. AICAR also improves lung condition of Flcn(f/f):SP-C-Cre mice. Our data suggest that lung cysts in BHD may result from an underlying defect in alveolar epithelial cell survival, attributable to FLCN regulation of the E-cadherin-LKB1-AMPK axis.Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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