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切口/马分泌酶抑制将肠道密室和腺瘤中的增殖细胞转化为杯状细胞
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
概括
在小肠中,阻断Notch通路将增殖细胞迅速转化为杯状细胞. 这一发现表明,玛分泌酶抑制剂可以治疗结直肠癌.
科学领域:
- 细胞生物学 细胞生物学
- 胃肠病学 胃肠病学
- 癌症研究 癌症研究
背景情况:
- 肠道上皮层通过隐藏体中的干细胞/祖细胞和体上的分化细胞来更新自身.
- 该Wnt信号通路对于细胞命运确定沿着密码-维卢斯轴至关重要.
- 目前正在调查Notch通路在肠道干细胞维护中的作用.
研究的目的:
- 调查Notch通路在维持肠道干细胞和祖细胞中的作用.
- 探索针对结直肠瘤中诺奇通路的治疗潜力.
主要方法:
- 在小鼠中条件去除Notch通路转录因子CSL/RBP-J.
- 使用玛分泌酶抑制剂的诺奇级联的药理抑制.
- 分析小杯细胞在小鼠肠道密室和腺瘤中的分化和增殖.
主要成果:
- 条件去除CSL/RBP-J诱导了繁殖密室细胞迅速,大规模地转化为杯状细胞.
- 马分泌酶抑制模仿了这种效应,诱导了杯状细胞的分化.
- 诺奇和Wnt通路协同作用,维持密室和腺瘤中的未分化,增殖细胞.
- 玛分泌酶抑制剂诱导了APC突变小鼠腺瘤中的杯状细胞分化.
结论:
- 协同激活Notch和Wnt信号对于维持肠道密室和腺瘤中的增殖细胞至关重要.
- 为阿尔茨海默病开发的玛分泌酶抑制剂显示出对结直肠瘤疾病的治疗策略的潜力.
相关概念视频
Notch 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...
Abnormal 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...
Notch 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...
Renewal 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,...
Role 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.
Role 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...

