PT  - JOURNAL ARTICLE
AU  - Eunseon Hur
AU  - Keun Young Chang
AU  - Eunjung Lee
AU  - Seung-Ki Lee
AU  - Hyunsung Park
TI  - Mitogen-Activated Protein Kinase Kinase Inhibitor PD98059 Blocks the <em>trans</em>-Activation but Not the Stabilization or DNA Binding Ability of Hypoxia-Inducible Factor-1α
AID  - 10.1124/mol.59.5.1216
DP  - 2001 May 01
TA  - Molecular Pharmacology
PG  - 1216--1224
VI  - 59
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/59/5/1216.short
4100  - http://molpharm.aspetjournals.org/content/59/5/1216.full
SO  - Mol Pharmacol2001 May 01; 59
AB  - 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.