Abstract
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 α-subunit of hypoxia-inducible factor-1 (HIF-1α), which acts as a heterodimerictrans-activator. Our results indicate that stabilization of HIF-1α 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-1α. 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-1α but it inhibits thetrans-activation ability of HIF-1α, 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-1α 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 thetrans-activation, but not the stabilization or DNA binding ability, of HIF-1α.
Footnotes
- Received August 28, 2000.
- Accepted January 26, 2001.
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Send reprint requests to: Dr. Hyunsung Park, Department of Life Science, University of Seoul, Seoul 130-743, Korea. E-mail:hspark{at}uoscc.uos.ac.kr
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This study was supported by a grant from the 1999 Korean National Cancer Control Program, Ministry of Health & Welfare (H.P.), Grant 1999-1-209-003-3 from the Korea Science and Engineering Foundation, and Grant 1998-003-F00261 from the Korea Research Foundation.
- The American Society for Pharmacology and Experimental Therapeutics
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