Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene.
The VHL tumor suppressor gene is inactivated in patients with von Hippel-Lindau disease and in most sporadic clear cell renal carcinomas. Although VHL protein function remains unclear, VHL does interact with the elongin BC subunits in vivo and regulates RNA polymerase II elongation activity in vitro by inhibiting formation of the elongin ABC complex. Expression of wild-type VHL in renal carcinoma cells with inactivated endogenous VHL resulted in unaltered in vitro cell growth and decreased vascular endothelial growth factor (VEGF) mRNA expression and responsiveness to serum deprivation. VEGF is highly expressed in many tumors, including VHL-associated and sporadic renal carcinomas, and it stimulates neoangiogenesis in growing solid tumors. Despite 5-fold differences in VEGF mRNA levels, VHL overexpression did not affect VEGF transcription initiation or elongation as would have been suggested by VHL-elongin association. These results suggest that VHL regulates VEGF expression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGF suppression, leading to formation of a vascular stroma.
Gnarra
J R
JR
Urologic Oncology Section, National Cancer Institute, Bethesda, MD 20892, USA.
Zhou
S
S
Merrill
M J
MJ
Wagner
J R
JR
Krumm
A
A
Papavassiliou
E
E
Oldfield
E H
EH
Klausner
R D
RD
Linehan
W M
WM
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002448:Cell Adhesion; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008025:Ligases; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011506:Proteins / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011506:Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human