@article{4a9a31da342c41ef9362f516c9fcc9d5,
title = "Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK",
abstract = "Spontaneous pneumothoraces due to lung cyst rupture afflict patients with the rare disease Birt-Hogg-Dub{\'e} (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 Flcnf/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.",
author = "Goncharova, {Elena A.} and Goncharov, {Dmitry A.} and James, {Melane L.} and Atochina-Vasserman, {Elena N.} and Victoria Stepanova and Hong, {Seung Beom} and Hua Li and Linda Gonzales and Masaya Baba and Linehan, {W. Marston} and Gow, {Andrew J.} and Susan Margulies and Susan Guttentag and Schmidt, {Laura S.} and Krymskaya, {Vera P.}",
note = "Funding Information: We thank Dr. Jeffrey A. Whitsett (Cincinnati Children{\textquoteright}s Hospital Medical Center) for generously providing SP-C-rtTA/tetO-Cre (line 2) mice and CCSP-rtTA/tetO-Cre (line 2) mice; Dr. Cheryl Walker (Texas A&M Health Science Center) for the generous gift of rat TSC2-null cells; Dr. Leslie A. Litzky (University of Pennsylvania) for help with tissue specimens from patients with BHD; Dr. Chang-Jiang Guo and Helen Abramova (Rutgers University) for excellent technical support; Ms. Sharmin Islam for preparing Figure S1 A; and Mr. Nathan Tessema Ersumo for exceptional help with Figures 1 and 2 , the graphical abstract, slider image, and technical assistance with the manuscript. This research was supported by the Intramural Research Program of NIH, Frederick National Laboratory for Cancer Research, and the Center for Cancer Research. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This work was supported by NIH/NHLBI RO1 HL110551 (to V.P.K.) and the Myrovlytis Trust (to S.-B.H. and V.P.K.). ",
year = "2014",
month = apr,
day = "24",
doi = "10.1016/j.celrep.2014.03.025",
language = "English (US)",
volume = "7",
pages = "412--423",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}