Von Hippel-Lindau protein and respiratory diseases

Abstract

Von Hippel-Lindau protein (pVHL) 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 pVHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor (HIF)-α, pVHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that pVHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of pVHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and FoxM1, leading to pulmonary arterial hypertension. Loss of pVHL 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 pVHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fibrosis. In alveolar epithelial cells, pVHL mediates Na-K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that pVHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.

Keywords: Von Hippel-Lindau protein; Lung cancer; Pulmonary fibrosis; Pulmonary hypertension

Core tip: Although von Hippel-Lindau protein (pVHL) was first identified as a tumor suppressor and is best known as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor (HIF)-α, recent studies suggest that pVHL contributes to many lung diseases in both HIF-dependent and HIF-independent pathways. Loss of pVHL promotes pulmonary arterial hypertension via activation of HIF. In lung cancer, loss of pVHL promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing cell proliferation and colonization. pVHL also induces fibronectin/integrin α5β1/focal adhesion kinase signaling to facilitate fibrogenesis. pVHL mediates Na-K-ATPase degradation to cause decreased edema clearance during hypoxia.