Abstract
Hypoxia-inducible factor 1 (HIF-1) plays a critical role in controlling oxygen delivery and metabolic adaptation to hypoxic conditions in hypoxic tumor cells. HIF-1 activation is initiated by several factors including mitogen-activated protein kinase (MAPK) superfamily. We have previously reported that mitogen-activated protein kinase phosphatase DUSP1 (MKP-1) was implicated in the negative regulation of HIF-1alpha subunit phosphorylation and HIF-1 activity. However, the molecular basis by which MKP-1 influences HIF-1 activity is not clarified. In this paper, we show that hypoxia transcriptionally induces MKP-1 expression in a time-dependent manner. Meanwhile, hypoxia also activates extracellular signal-regulated kinase (ERK) whose activity is enhanced or reduced by MKP-1 suppression or MKP-1 overexpression, respectively. We also show that suppression of MKP-1 expression facilitates the interaction between HIF-1alpha subunit and p300, a co-activator of HIF-1. Moreover, MKP-1 suppression leads to enhanced HIF-1 activity, which can be counteracted by PD98059, an ERK kinase inhibitor. Taken together, the results presented here suggest that hypoxia-induced MKP-1 protects overactivation of HIF-1 activation through inhibiting ERK kinase activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cell Line, Tumor
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Dual Specificity Phosphatase 1
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Flavonoids / pharmacology
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Humans
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Hypoxia / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immediate-Early Proteins / antagonists & inhibitors
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / physiology*
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JNK Mitogen-Activated Protein Kinases / biosynthesis
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JNK Mitogen-Activated Protein Kinases / genetics
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Nuclear Proteins / metabolism
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / physiology*
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Phosphorylation
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / physiology*
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Trans-Activators / metabolism
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
Substances
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Cell Cycle Proteins
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Flavonoids
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immediate-Early Proteins
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Nuclear Proteins
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Trans-Activators
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Transcription Factors
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Protein Tyrosine Phosphatases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one