Abstract
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that functions as a master regulator of oxygen homeostasis. The HIF-1alpha subunit is subjected to O(2)-dependent prolyl hydroxylation leading to ubiquitination by the von Hippel-Lindau protein (VHL)-Elongin C ubiquitin-ligase complex and degradation by the 26 S proteasome. In this study, we demonstrate that spermidine/spermine-N(1)-acetyltransferase (SSAT) 2 plays an essential role in this process. SSAT2 binds to HIF-1alpha, VHL, and Elongin C and promotes ubiquitination of hydroxylated HIF-1alpha by stabilizing the interaction of VHL and Elongin C. Multivalent interactions by SSAT2 provide a mechanism to ensure efficient complex formation, which is necessary for the extremely rapid ubiquitination and degradation of HIF-1alpha that is observed in oxygenated cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyltransferases / chemistry*
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Acetyltransferases / physiology*
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Cell Line
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Elongin
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Genetic Vectors
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Glutathione Transferase / metabolism
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Humans
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Hypoxia
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Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
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Models, Biological
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Oxygen / metabolism
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Proteasome Endopeptidase Complex / chemistry
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Protein Binding
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Transcription Factors / chemistry
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Two-Hybrid System Techniques
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Ubiquitin-Protein Ligases / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein / chemistry
Substances
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ELOC protein, human
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Elongin
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Transcription Factors
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Acetyltransferases
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diamine N-acetyltransferase
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Glutathione Transferase
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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VHL protein, human
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Oxygen