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Novel function of orphan nuclear receptor Nur77 in stabilizing hypoxia-inducible factor-1alpha
- Source :
- The Journal of biological chemistry. 279(51)
- Publication Year :
- 2004
-
Abstract
- Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis by inducing the expression of a broad range of genes in a hypoxia-dependent manner. Here, we show that the orphan nuclear receptor Nur77 is an important regulator of HIF-1alpha. Under hypoxic conditions, Nur77 protein and transcripts were induced in a time-dependent manner. When Nur77 was exogenously introduced, it enhanced the transcriptional activity of HIF-1, whereas the dominant negative Nur77 mutant abolished the function of HIF-1. The HIF-1alpha protein was greatly increased and completely localized in the nucleus when coexpressed with Nur77. The N-terminal transactivation domain of Nur77 was required and sufficient for the activation of HIF-1alpha. The association of HIF-1alpha with von Hippel-Lindau protein was not affected, whereas that with mouse double minute 2 (MDM2) was greatly reduced in the presence of Nur77. Further we found that the expression of MDM2 was repressed at transcription level in the presence of Nur77 as well as under hypoxic conditions. Finally, PD98059 decreased Nur77-induced HIF-1alpha stability and recovered MDM2 expression, indicating that the extracellular signal-regulated kinase pathway is critical in the Nur77-induced activation of HIF-1alpha. Together, our results demonstrate a novel function for Nur77 in the stabilization of HIF-1alpha and suggest a potential role for Nur77 in tumor progression and metastasis.
- Subjects :
- Transcriptional Activation
Receptors, Steroid
Time Factors
Nerve growth factor IB
Transcription, Genetic
Blotting, Western
Green Fluorescent Proteins
Receptors, Cytoplasmic and Nuclear
Biology
Transfection
Biochemistry
Cell Line
Transactivation
Mice
Cell Line, Tumor
Proto-Oncogene Proteins
Oxygen homeostasis
Nuclear Receptor Subfamily 4, Group A, Member 1
Animals
Humans
Immunoprecipitation
Enzyme Inhibitors
Neoplasm Metastasis
Hypoxia
Molecular Biology
Genes, Dominant
Cell Nucleus
Flavonoids
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Kinase
Reverse Transcriptase Polymerase Chain Reaction
Nuclear Proteins
Proto-Oncogene Proteins c-mdm2
Cell Biology
Hypoxia-Inducible Factor 1, alpha Subunit
Molecular biology
Neuron-derived orphan receptor 1
Protein Structure, Tertiary
DNA-Binding Proteins
Hypoxia-inducible factors
Nuclear receptor
Microscopy, Fluorescence
biology.protein
Disease Progression
Mdm2
Plasmids
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 279
- Issue :
- 51
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....0bb07ba0850a563988705515d36ff779