摘要
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.
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.
基金
Supported by Grants from Pulmonary Hypertension Association and American Lung Association to Dr.Guofei Zhou
