抑制性PASドメインタンパク質は,低酸素誘導性遺伝子発現の負の調節剤である
1Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Nature
|December 6, 2001
まとめ
新しいタンパク質である阻害性PAS (IPAS) は,低酸素誘導因子 (HIF) を負の調節し,遺伝子発現を制御します. IPASは腫瘍の成長と血管新生を阻害し,低酸素関連疾患に対する新しい治療標的を提供します.
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
- 腫瘍学 腫瘍学
背景:
- 遺伝子発現の変化は,低酸素 (低酸素症) に適応する鍵です.
- 低酸素誘導転写因子 (HIF) はこれらの適応反応を媒介する.
- 新しいタンパク質,抑制性PAS (IPAS) が特定され,構造的にはHIFに類似しています.
研究 の 目的:
- HIF媒介遺伝子発現を調節するIPASの機能を特徴付ける.
- 腫瘍の成長と血管新生におけるIPASの役割を調査する.
- 血管のフェノタイプを維持するIPASの生理学的役割を探求する.
主な方法:
- HIFの支配的ネガティブレギュレータとしてIPASを記述しました.
- 遺伝子の誘導を評価するために,肝腫細胞におけるIPASの産外発現.
- 腫瘍の成長と血管化を評価するためにマウスモデルを用いたインビボ研究.
- マウス組織 (小脳,角膜) でIPAS発現を調査した.
- マウスの角膜で反感覚オリゴヌクレオチドを用いて,血管新生とVEGF誘導を研究した.
主要な成果:
- IPASは,血管内皮成長因子 (VEGF) を含む低酸素適応性遺伝子の誘導を損なう.
- ヘパトーマ細胞におけるエクトピックIPAS発現は,腫瘍の成長と血管密度の低下につながった in vivo.
- IPASは主にプルキンジェ細胞と角膜上皮質で発現する.
- 角膜におけるIPAS発現は,低酸素状態の低VEGFレベルと相関する.
- マウスの角膜におけるIPASのアンチセンセスの阻害は,血管新生を誘発し,低酸素依存のVEGF発現を引き起こした.
結論:
- IPASは,HIF媒介による遺伝子発現の新たな負の調節剤として作用する.
- IPASは,腫瘍の血管新生と成長を抑制する上で重要な役割を果たします.
- IPASは,特に角膜における無血管現象の維持に寄与する.
- これらの発見は,血管新生を制御する新しいメカニズムを明らかにし,潜在的な治療戦略を提供します.
関連する概念動画
RNA Polymerase II Accessory Proteins
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
Cell Specific Gene Expression
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
Prokaryotic Transcriptional Activators and Repressors
The organization of prokaryotic genes in their genome is notably different from that of eukaryotes. Prokaryotic genes are organized, such that the genes for proteins involved in the same biochemical process or function are located together in groups. This group of genes, along with their regulatory elements, are collectively known as an operon. The functional genes in an operon are transcribed together to give a single strand of mRNA known as polycistronic mRNA.
Transcription of prokaryotic...
Transcription of prokaryotic...
Prokaryotic Transcriptional Activators and Repressors
The organization of prokaryotic genes in their genome is notably different from that of eukaryotes. Prokaryotic genes are organized, such that the genes for proteins involved in the same biochemical process or function are located together in groups. This group of genes, along with their regulatory elements, are collectively known as an operon. The functional genes in an operon are transcribed together to give a single strand of mRNA known as polycistronic mRNA.
Transcription of prokaryotic...
Transcription of prokaryotic...
Constitutive and Regulated Gene Expression
Gene expression in prokaryotes is governed by constitutive and regulated systems, allowing cells to balance the production of essential proteins with adaptive responses to environmental changes.Constitutive Gene ExpressionConstitutive, or housekeeping, genes are continuously expressed as they encode proteins vital for fundamental cellular processes. These include enzymes for glycolysis, ribosomal components for protein synthesis, and proteins involved in DNA replication. Their constant...
Repressible Operon: trp Operon
The trp operon in Escherichia coli exemplifies a repressible operon. It regulates the synthesis of tryptophan through repressor-mediated transcriptional control and attenuation. This dual regulatory mechanism ensures tryptophan biosynthesis occurs only when needed, conserving cellular resources.Structure of the trp OperonThe trp operon consists of five structural genes (trpE, trpD, trpC, trpB, and trpA) that encode enzymes for tryptophan biosynthesis. These genes are transcribed as a single...


