Significance of Notch signaling in cell fact determination of lung

Notch信号在肺细胞事实测定中的意义

• 批准号: 13670225
• 负责人: ITO Takaaki
• 金额: $ 2.3万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670225/
• 关键词: Lung epithelial cell; Lung carcinoma; Differentiation; Notch signaling; Basic helix-loop helix factor; Neuroendocrine cell; 転写因子; 間質性肺炎

The Notch signaling pathway plays an important role in determining cell fate of various cell system, and is considered to function in cell fate determination of the lung epithelia and lung carcinoma. And, the pathway works through regulating the network of proneural basic helix-loop helix factors.We did some experimental studies to clarify the significance of the Notch pathway in the lung, and gained the following results. 1) Immunohistochemical and Northern blot studies revealed that pulmonary neuroendocrine cells of the mouse (PNEC) showed positive staining for Mash1, Hes1(Cytoplasmic stain), Delta-like1(DII-1), but non-PNEC showed positive staining for Hes1 (nuclear and cytoplasmic stain), Notch-3, Jagged1-2. Expression of DII-1 is not detected in the lungs of Mash1 gene null mice, and expression of Notch1 is decreased in the lung of Hes1 gene null mice. 2) In human lung cancer cell lines, small cell carcinoma cells expressed hASH1, Hes1, DII-1, Jag1, and Jag2, but non-small cell carcinoma cells expressed Hes1, Notch1-Notch3, and Jag1. 3) Transfection of Notch1 gene and intracytoplasmic domain of Notch1 gene suppressed cell proliferation rate, abolished neuroendocrine differentiation and induced epithelial morphology with enhanced cell adhesiveness.Thus, theses studies support that the Notch signaling pathway and the basic helix-loop-helix factor network could be important in cell differentiation regulation in human lung diseases.

Notch信号通路在决定各种细胞系统的细胞命运中起重要作用，并且被认为在肺上皮和肺癌的细胞命运决定中起作用。本课题组对Notch通路在肺组织中的作用进行了实验研究，并取得了以下研究结果：1. Notch通路在肺组织中的作用机制1)免疫组化和北方印迹研究显示，小鼠肺神经内分泌细胞（PNEC）显示Mash 1、Hes 1（胞质染色）、Delta-like 1（DII-1）阳性染色，而非PNEC显示Hes 1（核和胞质染色）、Notch-3、Jagged 1 -2阳性染色。在Mash 1基因敲除小鼠的肺中未检测到DII-1的表达，而在Hes 1基因敲除小鼠的肺中Notch 1的表达降低。2)在人肺癌细胞系中，小细胞癌细胞表达hASH 1、Hes 1、DII-1、Jag 1和Jag 2，而非小细胞癌细胞表达Hes 1、Notch 1-Notch 3和Jag 1。3)Notch 1基因及其胞浆内结构域的转染抑制了细胞的增殖速率，消除了神经内分泌分化，诱导了上皮细胞的形态学改变并增强了细胞的增殖能力。因此，这些研究支持Notch信号通路和基本的螺旋-环-螺旋因子网络在人类肺部疾病的细胞分化调控中可能是重要的。

项目成果

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M.Kagoshima、T.Ito 等人：“脑信号蛋白在肺发育中的多样化功能和基因表达：脑信号蛋白在肺分支中的可能调节作用”Genes Cells。

N. Hiroi, T. Ito, et al.: "Rcd1 is a novel transcription cofactor that mediates retinoic acid-induced cell differentiation"EMBO J., 21(19). 5235-5244 (2002)

N. Hiroi、T. Ito 等人：“Rcd1 是一种介导视黄酸诱导的细胞分化的新型转录辅助因子”EMBO J.，21(19)。

T. Ito, et al.: "Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma."Endcr. Pathol.,. in press

T. Ito 等人：“肺神经内分泌细胞和小细胞癌中神经内分泌分化的机制。”Endcr。

T.Ito, et al.: "Modulation of pulmonary neuroendocrine cells in idiopathic interstitial pneumonia"Histol. Histopathol.. 17. 1121-1127 (2002)

T.Ito 等人：“特发性间质性肺炎中肺神经内分泌细胞的调节”Histol。

T. Ito, et al.: "Modulation of pulmonary neuroendocrine cells in idiopathic interstitial pneumonia."Histol. Histopathol.,17(4). 1121-1127 (2002)

T. Ito 等人：“特发性间质性肺炎中肺神经内分泌细胞的调节。”Histol。