Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth.

Mack FA, Rathmell WK, Arsham AM, Gnarra J, Keith B, Simon MC
Cancer Cell. 2003 3 (1): 75-88

PMID: 12559177 · PMCID: PMC4120823 · DOI:10.1016/s1535-6108(02)00240-4

Inactivation of the von Hippel-Lindau (VHL) gene is associated with the development of highly vascularized tumors. pVHL targets the alpha subunits of hypoxia inducible factor (HIF) for ubiquitin-mediated degradation in an oxygen-dependent manner. Although pVHL-deficient tumor cell lines demonstrate constitutive stabilization and activation of HIF, it has yet to be shown that loss of murine Vhl alone is sufficient to dysregulate HIF. We utilized a genetic approach to demonstrate that loss of Vhl is sufficient not only to stabilize HIF-alpha subunits under normoxia, but also fully activate HIF-mediated responses. These studies have implications for the hierarchy of signaling events leading to HIF stabilization, nuclear translocation, and target gene expression. We further demonstrate that loss of murine Vhl does not promote teratocarcinoma growth, indicating that other genetic changes must occur to facilitate Vhl-mediated tumorigenesis.

MeSH Terms (18)

Animals Apoptosis DNA-Binding Proteins Gene Expression Regulation, Neoplastic Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Ligases Mice Neoplasms, Experimental Nuclear Proteins Protein Subunits Teratocarcinoma Transcription Factors Tumor Cells, Cultured Tumor Suppressor Proteins Ubiquitin-Protein Ligases von Hippel-Lindau Disease Von Hippel-Lindau Tumor Suppressor Protein

Connections (1)

This publication is referenced by other Labnodes entities: