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-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.
authors.affiliation: 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.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Goncharova
authors.affiliation: 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.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Goncharov
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Melane L
authors.initials: ML
authors.lastname: James
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Atochina-Vasserman
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Stepanova
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Seung-Beom
authors.initials: SB
authors.lastname: Hong
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Gonzales
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Margulies
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Guttentag
authors.affiliation: 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.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.affiliation: 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.
authors.forename: Vera P
authors.initials: VP
authors.lastname: Krymskaya
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D058249:Birt-Hogg-Dube Syndrome / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C526060:Bhd protein, mouse; D015820:Cadherins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
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