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MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300
Journal article   Open access   Peer reviewed

MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300

Nianli Sang, Daniel P Stiehl, Jolene Bohensky, Irene Leshchinsky, Vickram Srinivas and Jaime Caro
The Journal of biological chemistry, v 278(16), pp 14013-14019
18 Apr 2003
DOI: https://doi.org/10.1074/jbc.M209702200
PMID: 12588875
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1074/jbc.M209702200View
Published, Version of Record (VoR) Open

Abstract

Up-Regulation Phosphorylation Luciferases - metabolism Humans Transcriptional Activation Recombinant Fusion Proteins - metabolism Hypoxia-Inducible Factor 1, alpha Subunit MAP Kinase Signaling System Dose-Response Relationship, Drug Transfection Time Factors Basic Helix-Loop-Helix Transcription Factors Protein Structure, Tertiary Cell Line Signal Transduction Glutathione Transferase - metabolism Nuclear Proteins - metabolism Plasmids - metabolism Blotting, Western Precipitin Tests Transcription Factors - metabolism Models, Biological Protein Binding Hypoxia Trans-Activators - metabolism Enzyme Activation HeLa Cells
Hypoxia-inducible factors (HIF) are a family of heterodimeric transcriptional regulators that play pivotal roles in the regulation of cellular utilization of oxygen and glucose and are essential transcriptional regulators of angiogenesis in solid tumor and ischemic disorders. The transactivation activity of HIF complexes requires the recruitment of p300/CREB-binding protein (CBP) by HIF-1 alpha and HIF-2 alpha that undergo oxygen-dependent degradation. HIF activation in tumors is caused by several factors including mitogen-activated protein kinase (MAPK) signaling. Here we investigated the molecular basis for HIF activation by MAPK. We show that MAPK is required for the transactivation activity of HIF-1 alpha. Furthermore, inhibition of MAPK disrupts the HIF-p300 interaction and suppresses the transactivation activity of p300. Overexpression of MEK1, an upstream MAPK activator, stimulates the transactivation of both p300 and HIF-1 alpha. Interestingly, the C-terminal transactivation domain of HIF-1 alpha is not a direct substrate of MAPK, and HIF-1 alpha phosphorylation is not required for HIF-CAD/p300 interaction. Taken together, our data suggest that MAPK signaling facilitates HIF activation through p300/CBP.

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Web of Science research areas
Biochemistry & Molecular Biology
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