Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1α

被引:106
作者
Hur, E
Chang, KY
Lee, E
Lee, SK
Park, H [1 ]
机构
[1] Seoul Univ, Dept Life Sci, Seoul 130743, South Korea
[2] Seoul Natl Univ, Coll Pharm, Seoul, South Korea
关键词
D O I
10.1124/mol.59.5.1216
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Under low oxygen tension, cells increase the transcription of specific genes that are involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression primarily depends on the stabilization of the alpha -subunit of hypoxia-inducible factor-1 (HIF-1 alpha), which acts as a heterodimeric transactivator. Our results indicate that stabilization of HIF-1 alpha protein by treatment of proteasome inhibitors, is not sufficient for hypoxia-induced gene activation, and an additional hypoxia-dependent modification is necessary for gene expression by HIF-1 alpha. Here, we demonstrate that mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor PD98059 does not change either the stabilization or DNA binding ability of HIF-1 alpha but it inhibits the trans-activation ability of HIF-1 alpha, thereby it reduces the hypoxia-induced transcription of both an endogenous target gene and a hypoxia-responsive reporter gene. We found that hypoxia induced p42/p44 mitogen-activated protein kinases (MAPKs) that are target protein kinases of MEK-1, and that expression of dominant-negative p42 and p44 MAPK mutants reduced HIF-1-dependent transcription of the hypoxia-responsive reporter gene. Our results are the first to identify that hypoxia-induced trans-activation ability of HIF-1 alpha is regulated by different mechanisms than its stabilization and DNA binding, and that these processes can be experimentally dissociated. MEK-1/p42/p44 MAPK regulates the trans-activation, but not the stabilization or DNA binding ability, of HIF-1 alpha.
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页码:1216 / 1224
页数:9
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