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Notch/gamma-secretaseの阻害により,腸内クリプトとアデノマの増殖細胞がゴブレット細胞に変わります
Johan H van Es1, Marielle E van Gijn, Orbicia Riccio
1Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
Nature
|June 17, 2005
まとめ
小腸では,Notch経路を遮断すると,増殖細胞を迅速にゴブレット細胞に変換します. この発見は,ガンマ分泌酵素阻害剤が結腸直腸癌の治療に役立つことを示唆しています.
科学分野:
- 細胞生物学 細胞生物学
- 胃腸内科 胃腸内科
- がん研究 がん研究
背景:
- 腸内皮質は,クリプトの幹細胞/祖先細胞,およびビリルの分化細胞を通じて再生します.
- Wnt信号伝達経路は,クリプト・ヴィルス軸に沿った細胞運命を決定する上で極めて重要です.
- 腸の幹細胞維持におけるノッチ経路の役割は調査中です.
研究 の 目的:
- 腸の幹細胞と祖先細胞の維持におけるノッチ経路の役割を調査する.
- 結腸直腸新生病におけるノッチ経路を標的とした治療の可能性を調査する.
主な方法:
- ネズミにおけるノッチ経路の転写因子CSL/RBP-Jの条件付き除去.
- ガンマ分泌酵素阻害剤を用いたノッチカスケードの薬理学的阻害.
- ネズミの腸内クリプトとアデノマにおけるコップレット細胞の分化と増殖の分析.
主要な成果:
- CSL/RBP-Jの条件付きの除去は,増殖性暗号細胞の急速で大規模な変換を誘導し,ゴブレット細胞にしました.
- ガンマ分泌酵素の阻害は,この効果を模倣し,ゴブレット細胞の分化を引き起こした.
- Notch 経路と Wnt 経路は協調的に作用し,暗号やアデノマの無差別で増殖する細胞を維持します.
- ガンマ分泌酵素阻害剤は,Apc変異性マウス腺腫におけるゴブレット細胞の微分化を誘導した.
結論:
- NotchとWntのシグナル伝達の協調的な活性化は,腸の密室と腺腫の増殖細胞を維持するために不可欠です.
- アルツハイマー病のために開発されたガンマ分泌酵素阻害剤は,大腸直腸腫瘍性疾患の治療戦略として潜在力を示しています.
関連する概念動画
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
01:23Renewal of Intestinal Stem Cells
The intestinal epithelial lining rapidly renews every 4 to 5 days. The renewal is facilitated by intestinal stem cells (ISCs) located at the base of the crypt– a gland located at the bottom of each villus. ISCs divide asymmetrically to form new stem cells and progenitor daughter cells. The daughter cells are called transit-amplifying (TA) cells which move upwards along the crypt and either differentiate into absorptive cells– the enterocytes or secretory cells– including the goblet,...
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...