ARD1媒介アセチル化によるHIF-1αの調節と不安定化
Joo Won Jeong1, Moon Kyoung Bae, Mee Young Ahn
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 151-742, Seoul, South Korea.
Cell
|December 5, 2002
まとめ
ARD1は低酸素誘導因子-1α (HIF-1α) をアセチル化し,pVHLとの相互作用を促し,プロテアソマル分解を促します. このARD1によるアセチル化は,HIF-1αの安定性を制御する重要な規制メカニズムである.
科学分野:
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
- バイオケミストリー バイオケミストリー
背景:
- 低酸素誘導因子1 (HIF-1) は,低酸素状態への細胞適応に不可欠です.
- HIF-1αの安定性は,プロリル水酸化と,その後pVHL複合体によるユビキチン化によって調節される.
研究 の 目的:
- HIF-1αの安定性を調節するARD1の役割を調査する.
- ARD1がHIF-1alpha.のタンパク質アセチルトランスフェラーゼとして機能するかどうかを判断する.
主な方法:
- 共同免疫プレシピテーションは,タンパク質の相互作用を評価するための測定法です.
- ウェスタン・ブロッティングは,タンパク質のレベルと変化を検知します.
- インビトロアセチル化アッセイ.
主要な成果:
- ARD1は哺乳類の細胞でHIF-1αに直接結合する.
- ARD1は,HIF-1alpha.へのタンパク質アセチルトランスフェラーゼ活性を示す.
- ARD1媒介によるアセチル化は,pVHLとのHIF-1α相互作用を強化し,そのユビキチン化を促進する.
結論:
- ARD1は,HIF-1αの安定性を調節するタンパク質アセチルトランスフェラーゼとして作用する.
- ARD1によるHIF-1alphaのアセチル化は,そのタンパク質分解の重要なステップです.
- ARD1媒介によるアセチル化は,HIF-1αホメオスタシスの新しい規制メカニズムを提供します.
関連する概念動画
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
01:24Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
01:23Regulation of Expression at Multiple Steps
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the addition of a...