Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK

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, Vera P. Krymskaya

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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 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.

Original languageEnglish
Pages (from-to)412-423
Number of pages12
JournalCell Reports
Volume7
Issue number2
DOIs
Publication statusPublished - 24 Apr 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Goncharova, E. A., Goncharov, D. A., James, M. L., Atochina-Vasserman, E. N., Stepanova, V., Hong, S. B., ... Krymskaya, V. P. (2014). Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK. Cell Reports, 7(2), 412-423. https://doi.org/10.1016/j.celrep.2014.03.025