The von Hippel-Lindau protein interacts with heteronuclear ribonucleoprotein a2 and regulates its expression.
The product of the von Hippel-Lindau (VHL) tumor suppressor gene, pVHL, functions as a ubiquitin-protein isopeptide ligase in regulating HIF-1 protein turnover, thus accounting for the increased transcription of hypoxia-inducible genes that accompanies VHL mutations. The increased vascular endothelial 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, heteronuclear ribonucleoprotein (hnRNP) A2, is specifically increased in pVHL-deficient cell lines. Enhanced hnRNP A2 expression was apparent in all cell fractions, including polysomes, where a similar modest effect on hnRNP L (a GLUT-1 and VEGF 3'-untranslated region-binding protein), was seen. Steady state levels of hnRNP A2 mRNA were unaffected. Regulation of hnRNP A2 levels correlated with the ability of pVHL to bind elongin C. Proteasome inhibition of cells expressing wild type pVHL selectively increased cytoplasmic hnRNP A2 levels to that seen in pVHL-deficient cells. Finally, an in vivo interaction 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 interactions as well as functioning proteasomes.
Pioli
P A
PA
Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Rigby
W F
WF
D002292:Carcinoma, Renal Cell / Q000235:genetics; D003546:Cysteine Endopeptidases; D000075065:Elongin; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051272:Glucose Transporter Type 1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D008025:Ligases / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease
C000616395:ELOC protein, human; D000075065:Elongin; D051272:Glucose Transporter Type 1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D012261:Ribonucleoproteins; C495677:SLC2A1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C439768:hnRNP A2; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; C497446:VHL protein, human