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Cell Rep. 2014 Apr 24;7(2):412-23. doi: 10.1016/j.celrep.2014.03.025. Epub 2014 Apr 13.

Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK.

Author information

1
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.
2
Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
4
Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
5
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
6
Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
7
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 20892, USA.
9
Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: krymskay@mail.med.upenn.edu.

Abstract

Spontaneous 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.

PMID:
24726356
PMCID:
PMC4034569
DOI:
10.1016/j.celrep.2014.03.025
[Indexed for MEDLINE]
Free PMC Article

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