Hu protein R-mediated posttranscriptional regulation of VEGF expression in rat gastrocnemius muscle.
Hypoxic exercise increases VEGF expression and the formation of new capillaries. In addition to hypoxia-inducible factor regulation at the transcriptional level, VEGF message stabilization is also a key regulatory step for VEGF expression. In vitro experiments have identified Hu protein R (HuR) as a potential posttranscriptional regulator of VEGF gene expression. Here, we report that in rat skeletal muscle (gastrocnemius muscle), 1) HuR binds to a known regulatory sequence located in the VEGF mRNA 3'-untranslated region (1,631-1,678 bp); 2) HuR specifically binds to the A/U-rich element AUUUUA (1,665-1,670 bp) and an additional A/U-rich region containing the consensus sequence UUUUUUA (1,658-1,664 bp); 3) binding of HuR to VEGF mRNA is seen already 5 min after acute ischemia, remaining elevated throughout a 60-min ischemic period; 4) a second inducible HuR-VEGF mRNA binding factor is evident 30 and 60 min postischemia; and 5) VEGF mRNA and protein levels are increased 20 and 30 min, respectively, after acute ischemia. These findings suggest that acute ischemia induces a rapid binding of HuR to the VEGF mRNA 3'-untranslated region. In skeletal muscle, this specific protein-RNA interaction may be an important posttranscriptional regulatory mechanism for increasing VEGF expression in response to hypoxia or acute ischemia.
Tang
Kechun
K
Division of Physiology, Department of Medicine, University of California, La Jolla 92093, USA. ktang@ucsd.edu
Breen
Ellen C
EC
Wagner
Peter D
PD
D020413:3' Untranslated Regions / Q000235:genetics; D000208:Acute Disease; D000818:Animals; D000954:Antigens, Surface; D001665:Binding Sites / Q000235:genetics; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology; D007511:Ischemia / Q000503:physiopathology; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020413:3' Untranslated Regions; D000954:Antigens, Surface; 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