U19/Eaf2 binds to and stabilizes von hippel-lindau protein.

Studies have firmly established a key regulatory role for the tumor suppressor pVHL in the regulation of the vascular system and normal spermatogenesis. Here, we report that knockout of the newly identified tumor suppressor U19/Eaf2 also caused vascular system abnormalities and aspermatogenesis, suggesting a potential link between U19/Eaf2 and pVHL. ...
Coimmunoprecipitation and in vitro binding assays showed an association between U19/Eaf2 and pVHL, whereas deletion mutagenesis revealed the requirement of the NH(2) terminus of U19/Eaf2 and both the alpha and beta domains of pVHL for this binding. U19/Eaf2 stabilizes pVHL, as shown by protein stability and pulse-chase studies. Testes and mouse embryonic fibroblasts (MEF) derived from U19/Eaf2 knockout mice expressed reduced levels of pVHL, indicating that full in vivo expression of pVHL indeed requires U19/Eaf2. As expected, U19/Eaf2 knockout MEF cells exhibited an increased level and activity of hypoxia-inducible factor 1alpha (HIF1alpha), a protein typically regulated via a pVHL-mediated degradation pathway. Furthermore, angiogenesis in a Matrigel plug assay was significantly increased in U19/Eaf2 knockout mice. The above observations argue that U19/Eaf2 can modulate HIF1alpha and angiogenesis, possibly via direct binding and stabilization of pVHL.
Mesh Terms:
Animals, COS Cells, Cercopithecus aethiops, Gene Deletion, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Physiologic, Nuclear Proteins, Protein Binding, Rats, Trans-Activators, Transfection, Von Hippel-Lindau Tumor Suppressor Protein
Cancer Res.
Date: Mar. 15, 2009
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