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

Goncharova, Elena A.; Goncharov, Dmitry A.; James, Melane L.; Atochina‐Vasserman, Elena N.; Stepanova, Victoria; Hong, Seung-Beom; Li, Hua; Gonzales, Linda K; M, Baba; Linehan, W. Marston; Gow, Andrew J.; Margulies, Susan S.; Guttentag, Susan H.; Schmidt, Laura S.; Krymskaya, Vera P.

doi:10.1016/j.celrep.2014.03.025

Cited by 82 publications

(101 citation statements)

References 49 publications

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“…85,86 Increased cell-cell adhesions were reported in FLCN -deficient lung cell lines in vitro 87 and marked reduction in E-cadherin expression at adherens junctions and increased alveolar apoptosis were observed in lungs of mice with lung-targeted Flcn inactivation. 88 These findings support a role for FLCN in maintaining critical cell-cell adhesions for maintenance of lung and kidney epithelial cell integrity ( Figure 7 ).…”

Section: Potential Pathways In Bhd Tumorigenesissupporting

confidence: 71%

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

2015

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Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk to develop benign, cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumors. Bilateral multifocal renal tumors that develop in BHD syndrome are most frequently hybrid oncocytic tumors and chromophobe renal carcinoma, but may present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome. BHD-associated renal tumors show inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumor suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3/TFEB transcriptional activity, amino acid-dependent mTOR activation through Rag GTPases, TGF-β signaling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumors. Further understanding of the FLCN pathway will hopefully lead to the development of effective forms of therapy for this disease.

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Section: Potential Pathways In Bhd Tumorigenesissupporting

confidence: 71%

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

2015

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“…It results from mutations of the Folliculin ( FLCN ) gene, a tumor suppressor gene (53, 54). The exact mechanism of pulmonary cyst formation is unclear, but may involve alterations in the mTOR pathway (55), altered cell-cell adhesion resulting in increased vulnerability to mechanical forces (56), impaired LKB1-AMPK signaling (57) and disordered extracellular matrix remodeling involving MMP’s (58). …”

Section: Introductionmentioning

confidence: 99%

Spontaneous pneumothorax in diffuse cystic lung diseases

Cooley

Lee

Gupta

2017

Current Opinion in Pulmonary Medicine

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Purpose of review Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of disorders with varying pathophysiologic mechanisms that are characterized by the presence of air-filled lung cysts. These cysts are prone to rupture, leading to the development of recurrent spontaneous pneumothoraces. In this article, we review the epidemiology, clinical features, and management DCLD-associated spontaneous pneumothorax, with a focus on lymphangioleiomyomatosis (LAM), Birt-Hogg-Dubé syndrome (BHD), and pulmonary Langerhans cell histiocytosis (PLCH). Recent findings DCLDs are responsible for approximately 10% of apparent primary spontaneous pneumothoraces. CT screening for DCLDs (BHD, LAM, and PLCH) following the first spontaneous pneumothorax has recently been shown to be cost-effective and can help facilitate early diagnosis of the underlying disorders. Patients with DCLD-associated spontaneous pneumothorax have a very high rate of recurrence, and thus pleurodesis should be considered following the first episode of spontaneous pneumothorax in these patients, rather than waiting for a recurrent episode. Prior pleurodesis is not a contraindication to future lung transplant. Summary Although DCLDs are uncommon, spontaneous pneumothorax is often the sentinel event that provides an opportunity for diagnosis. By understanding the burden and implications of pneumothoraces in DCLDs, clinicians can facilitate early diagnosis and appropriate management of the underlying disorders.

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“…Loss of FLCN induced alveolar epithelial dysfunction. In FLCN-null mice, impairment of AMPK activation increases the level of cleaved caspase-3, which leads to alveolar epithelial apoptosis35. Another study showed that AMPK activator AICAR induces apoptotic cell death and diminishes adiposity in adipocytes36.…”

Section: Discussionmentioning

confidence: 99%

Effects of Bisphenol A Metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene on Lung Function and Type 2 Pulmonary Alveolar Epithelial Cell Growth

Liu

Lee

et al. 2016

Sci Rep

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Bisphenol A (BPA) is recognized as a major pollutant worldwide. 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is a major active metabolite of BPA. The epidemiological and animal studies have reported that BPA is harmful to lung function. The role of MBP in lung dysfunction after BPA exposure still remains unclear. This study investigated whether MBP would induce lung alveolar cell damage and evaluated the role of MBP in the BPA exposure-induced lung dysfunction. An in vitro type 2 alveolar epithelial cell (L2) model and an ex vivo isolated reperfused rat lung model were used to determine the effects of BPA or MBP on cell growth and lung function. MBP, but not BPA, dose-dependently increased the mean artery pressure (Pa), pulmonary capillary pressure (Pc), pulmonary capillary filtration coefficient (Kfc), and wet/dry weight ratio in isolated reperfused rat lungs. MBP significantly reduced cell viability and induced caspases-3/7 cleavage and apoptosis and increased AMP-activated protein kinas (AMPK) phosphorylation and endoplasmic reticulum (ER) stress-related molecules expression in L2 cells, which could be reversed by AMPK-siRNA transfection. These findings demonstrated for the first time that MBP exposure induced type 2 alveolar cell apoptosis and lung dysfunction through an AMPK-regulated ER stress signaling pathway.

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

Cited by 82 publications

References 49 publications

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

Spontaneous pneumothorax in diffuse cystic lung diseases

Effects of Bisphenol A Metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene on Lung Function and Type 2 Pulmonary Alveolar Epithelial Cell Growth

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