von Hippel-Lindau tumor suppressor protein regulates the assembly of intercellular junctions in renal cancer cells through hypoxia-inducible factor-independent mechanisms.
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is responsible for the development of renal cell cancers (RCC), pheochromocytomas, and tumors in other organs. The best known function of VHL protein (VHL) is to target the hypoxia-inducible factor (HIF) for proteasome degradation. VHL is also required for the establishment of an epithelial-like cell shape in otherwise fibroblastic-like RCC cell lines. However, the underlying mechanisms and whether this is linked to HIF remain undetermined. Because the breakage of intercellular junctions induces a fibroblastic-like phenotype in multiple cancer cell models, we hypothesized that VHL may be required for the assembly of intercellular junctions in RCC cells. Our experiments showed that VHL in RCC cell lines is necessary for the normal organization of adherens and tight intercellular junctions, the maintenance of cell polarity, and control of paracellular permeability. Additionally, 786-O cells reconstituted with wild-type VHL and with a constitutively active form of HIF-2alpha did not reproduce any of the phenotypic alterations of VHL-negative cells. In summary, we show that VHL inactivation in RCC cells disrupts intercellular junctions and cell shape through HIF-independent events, supporting the concept that VHL has additional functions beside its role in the regulation of HIF.
Calzada
Maria J
MJ
Servicio de Inmunología, Hospital de la Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Diego de León 62, 28006 Madrid, Spain.
Esteban
Miguel A
MA
Feijoo-Cuaresma
Monica
M
Castellanos
Maria C
MC
Naranjo-Suárez
Salvador
S
Temes
Elisa
E
Méndez
Fernando
F
Yánez-Mo
Maria
M
Ohh
Michael
M
Landázuri
Manuel O
MO
D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000473:pathology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D005353:Fibronectins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1