HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1alpha degradation.
Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis. In normoxia, HIF-1alpha is a short lived protein, whereas hypoxia rapidly increases HIF-1alpha protein levels by relaxing its ubiquitin-proteasome-dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF-1alpha, does not modulate the degradation/stabilization ... profile of HIF-1alpha. However, we present evidence that the rate of HIF-1alpha degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF-1alpha is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF-1-dependent transcriptional activity. In keeping with these findings, we postulate that HIF-1alpha is targetted to the proteasome via a HIF-1alpha proteasome targetting factor (HPTF) which expression is directly under the control of HIF-1-mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel-Lindau protein (pVHL).
Mesh Terms:
Cell Hypoxia, Cysteine Endopeptidases, DNA-Binding Proteins, Dactinomycin, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Ligases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Multienzyme Complexes, Nuclear Proteins, Nucleic Acid Synthesis Inhibitors, Oxygen, Phosphorylation, Precipitin Tests, Proteasome Endopeptidase Complex, Proteins, RNA, Messenger, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Cell Hypoxia, Cysteine Endopeptidases, DNA-Binding Proteins, Dactinomycin, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Ligases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Multienzyme Complexes, Nuclear Proteins, Nucleic Acid Synthesis Inhibitors, Oxygen, Phosphorylation, Precipitin Tests, Proteasome Endopeptidase Complex, Proteins, RNA, Messenger, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
FEBS Lett.
Date: Feb. 23, 2001
PubMed ID: 11226425
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