Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although p VHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor(HIF)-α, p VHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that p VHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of p VHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and Fox M1, leading to pulmonary arterial hypertension. Loss of p VHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of p VHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fi-brosis. In alveolar epithelial cells, p VHL mediates Na, K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that p VHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.
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