The von Hhippel-Lindau protein interacts with heteronuclear ribonucleoprotein A2 and regulates its expression

The product of the von Hippel-Lindau (VHL) tumor suppressor gene, pVHL, fun ctions as a ubiquitin-protein isopeptide ligase in regulating HIF-1 protein turnover, thus accounting for the increased transcription of hypoxia-induc ible genes that accompanies VHL mutations. The increased vascular endotheli al growth factor mRNA stability in cells lacking pVHL has been hypothesized to be due to a similar regulation of an RNA-binding protein. We report the expression of the GLUT-1 3'-untranslated region RNA-binding protein, heter onuclear ribonucleoprotein (hnRNP) A2, is specifically increased in pVHL-de ficient cell lines. Enhanced hnRNP A2 expression was apparent in all cell f ractions, including polysomes, where a similar modest effect on hnRNP L (a GLUT-1 and VEGF 3'-untranslated region-binding protein), was seen. Steady s tate levels of hnRNP A2 m-RNA were unaffected. Regulation of hnRNP A2 level s correlated with the ability of pVHL to bind elongin C. Proteasome inhibit ion of cells expressing wild type pVHL selectively increased cytoplasmic hn RNP A2 levels to that seen in pVHL-deficient cells. Finally, an in vivo int eraction between pVHL and hnRNP A2 was demonstrated in both the nucleus and the cytoplasm. Collectively, these data indicate that hnRNP A2 expression is regulated by pVHL in a manner that is dependent on elongin C interaction s as well as functioning proteasomes.