Stabilization of hepatocyte growth factor mRNA by hypoxia-inducible factor 1.
Hypoxia regulates expression of hepatocyte growth factor (HGF) by increasing its transcription and by stabilizing its mRNA. Despite the pivotal role of hypoxia-inducible factor 1 (HIF-1) in transcriptional activation of hypoxia-responsive genes, it is not known whether HIF-1 mediates hypoxia-induced stabilization of HGF mRNA. We constructed adenoviral vectors expressing either the wild-type HIF-1alpha (Ad2/HIF-1alpha/FL), a constitutively stable hybrid form of HIF-1alpha (Ad2/HIF-1alpha/VP16), or no transgene (Ad2/CMVEV). In rat glioma (C6) cells, human glioma (U251) cells human cardiac, vascular smooth muscle, and endothelial cells, infection with Ad2/HIF-1alpha/VP16 or Ad2/HIF-1alpha/FL increased HGF expression at both the mRNA and protein levels. Under normoxic conditions, the half-life of HGF mRNA was 43 min in C6 and U251 cells. Hypoxia and Ad2/HIF-1alpha/VP16 increased the half-life of HGF mRNA to 3.2 and 2.8 h, respectively, while Ad2/CMVEV had no effect. These studies are the first to demonstrate that overexpression of HIF-1alpha increases HGF mRNA stability. Our results also suggest that stabilization of HGF mRNA by hypoxia is mediated, at least in part, by HIF-1.
Chu
Sheng-Hua
SH
Department of Neurosurgery, No. 3 People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. shenghuachu@126.com
Feng
Dong-Fu
DF
Ma
Yan-Bin
YB
Zhu
Zhi-An
ZA
Zhang
Hong
H
Qiu
Jian-Hua
JH
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor