Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR.
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor whose expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. Here we show that HuR binds with high affinity and specificity to the element that regulates VEGF mRNA stability by hypoxia. Inhibition of HuR expression abrogates the hypoxia-mediated increase in VEGF mRNA stability. Overexpression of HuR increases the stability of VEGF mRNA. However, this only occurs efficiently in hypoxic cells. We further show that the stabilization of VEGF mRNA can be recapitulated in vitro. Using an S-100 extract, we show that the addition of recombinant HuR stabilizes VEGF mRNA markedly. These data support the critical role of HuR in mediating the hypoxic stabilization of VEGF mRNA by hypoxia.
Levy
N S
NS
Cardiology Division, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Chung
S
S
Furneaux
H
H
Levy
A P
AP
D000954:Antigens, Surface; D001483:Base Sequence; D002478:Cells, Cultured; D016373:DNA, Antisense; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006207:Half-Life; D000860:Hypoxia / Q000378:metabolism*; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000954:Antigens, Surface; D016373:DNA, Antisense; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors