Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation

Cell. 2002 Nov 27;111(5):709-20. doi: 10.1016/s0092-8674(02)01085-1.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Cell Hypoxia
  • Cell Line
  • Cell Line, Transformed
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoribonucleases / metabolism*
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Luminescent Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Oxygen / metabolism
  • Phosphoprotein Phosphatases
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • RNA-Binding Proteins*
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Luminescent Proteins
  • RNA-Binding Proteins
  • Recombinant Proteins
  • Transcription Factors
  • Green Fluorescent Proteins
  • Endoribonucleases
  • Phosphoprotein Phosphatases
  • PPP1R8 protein, human
  • Oxygen