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

• Published in: Cell Vol. 111; no. 5; pp. 709 - 720
• Main Authors: Jeong, Joo Won, Bae, Moon Kyoung, Ahn, Mee Young, Kim, Se Hee, Sohn, Tae Kwon, Bae, Myung Ho, Yoo, Mi Ae, Song, Eun Joo, Lee, Kong Joo, Kim, Kyu Won
• Format: Journal Article
• Language: English
• Published: United States 27.11.2002
• Subjects: 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; Recombinant Proteins - metabolism; RNA-Binding Proteins; Sequence Deletion; Sequence Homology, Amino Acid; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Tumor Cells, Cultured
• ISSN: 0092-8674

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.