| RRC ID |
41461
|
| 著者 |
Sato M, Tanaka T, Maeno T, Sando Y, Suga T, Maeno Y, Sato H, Nagai R, Kurabayashi M.
|
| タイトル |
Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway.
|
| ジャーナル |
Am J Respir Cell Mol Biol
|
| Abstract |
Hypoxia is a potent inducer of tumor angiogenesis, the process of which is mostly mediated by induction of vascular endothelial growth factor (VEGF). In this study, we investigated the effect of hypoxia on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and endothelial PAS domain protein-1 (EPAS1). These two similar but distinct basic helix-loop-helix-PAS proteins have been postulated to activate VEGF expression in response to hypoxia. We showed that EPAS1, but not HIF-1alpha, is abundantly expressed in human lung adenocarcinoma A549 cells. Exposure of cultured A549 cells to hypoxia increased EPAS1 mRNA and protein levels. A specific inhibitor for Src family kinases, PP1, abolished the hypoxia-induced expression of EPAS1. Transient transfection assays revealed that forced expression of EPAS1 increased the reporter gene activity driven by EPAS1 promoter as well as by VEGF promoter. Finally, overexpression of EPAS1 by infection of adenoviral vector expressing EPAS1 cDNA evidently induced the endogenous EPAS1 gene expression. Together, these data demonstrate Src family kinases mediate the hypoxia-mediated EPAS1 gene expression, which in turn positively autoregulates its own expression. Given an EPAS1 as a potent activator of the VEGF gene, these findings will provide a novel insight into the mechanisms underlying the enhancement of growth property of EPAS1-expressing tumor cells under the hypoxic environment.
|
| 巻・号 |
26(1)
|
| ページ |
127-34
|
| 公開日 |
2002-1-1
|
| DOI |
10.1165/ajrcmb.26.1.4319
|
| PMID |
11751212
|
| MeSH |
Adenocarcinoma / metabolism*
Adenoviridae / genetics
Basic Helix-Loop-Helix Transcription Factors
Blotting, Northern
Blotting, Western
DNA, Complementary / metabolism
Endothelial Growth Factors / biosynthesis
Endothelial Growth Factors / genetics
Endothelium, Vascular / metabolism*
Enzyme Inhibitors / pharmacology
Humans
Hypoxia
Luciferases / genetics
Luciferases / metabolism
Lung Neoplasms / metabolism*
Lymphokines / biosynthesis
Lymphokines / genetics
Models, Biological
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins pp60(c-src) / physiology
Pyrazoles / pharmacology
Pyrimidines / pharmacology
RNA, Messenger / metabolism
Signal Transduction
Time Factors
Trans-Activators / biosynthesis*
Trans-Activators / chemistry*
Trans-Activators / genetics
Transcription, Genetic
Transfection
Tumor Cells, Cultured
Up-Regulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
|
| IF |
5.373
|
| 引用数 |
43
|
|
WOS 分野
|
RESPIRATORY SYSTEM
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
A549(RCB0098) |
