Abstract
Hypoxia-inducible factor 1 (HIF-1) plays a central role in cellular adaptation to changes in oxygen availability. Recently, prolyl hydroxylation was identified as a key regulatory event that targets the HIF-1alpha subunit for proteasomal degradation via the pVHL ubiquitination complex. In this report, we reveal an important function for ARD1 in mammalian cells as a protein acetyltransferase by direct binding to HIF-1alpha to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1alpha with pVHL and HIF-1alpha ubiquitination, suggesting that the acetylation of HIF-1alpha by ARD1 is critical to proteasomal degradation. Therefore, we have concluded that the role of ARD1 in the acetylation of HIF-1alpha provides a key regulatory mechanism underlying HIF-1alpha stability.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Amino Acid Sequence
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Animals
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Cell Hypoxia
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Cell Line
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Cell Line, Transformed
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endoribonucleases / metabolism*
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Gene Expression Regulation
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Green Fluorescent Proteins
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Luminescent Proteins / metabolism
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Mice
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Molecular Sequence Data
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Oxygen / metabolism
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Phosphoprotein Phosphatases
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Protein Processing, Post-Translational
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Protein Structure, Tertiary
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RNA-Binding Proteins*
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Recombinant Proteins / metabolism
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Sequence Deletion
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Sequence Homology, Amino Acid
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Luminescent Proteins
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RNA-Binding Proteins
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Recombinant Proteins
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Transcription Factors
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Green Fluorescent Proteins
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Endoribonucleases
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Phosphoprotein Phosphatases
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PPP1R8 protein, human
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Oxygen