Notch in hematopoiesis

造血缺损

• 批准号: 11670980
• 负责人: CHIBA Shigeru
• 金额: $ 2.37万
• 依托单位: University of Tokyo Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670980/
• 关键词: Notch; signal; cleavage; phosphorylation; hematopoiesis; differentiation inhibition; GATA2; Notchリガンド; DSL蛋白質; 分化抑制

[Purpose] Aims of this study were to understand (1) how the signal through the Notch receptor is generated and (2) the mechanism of Notch-induced inhibition of differentiation in hematopoietic cells.[Methods](1) Cleavage, translocation and phosphorylation of the Notch2 molecule were studied using specific antibodies against Notch2.(2) Effect of activated form of Notch1 (aN1) on differentiation of hematopoietic cells was studied. Next, changes in expression of hematopoietic transcription factors (HTF), which were involved in the differentiation and growth of hematopoietic cells, were examined. Finally, dominant-negative form of GATA (DN-GATA) and PU.1 were expressed in a cell line expressing aN1, and the resulting trasnfectants were used to study the response to differentiation stimulation.[Results and Discussions](1-1) The transmembrane subunit of the Notch2 molecule was cleaved. Resulting molecules comprising the intracellular region were then shortly entered the nucleus.(1-2) The tra … More nslocated Notch2 molectules were phosphorylated.(1-3) Notch ligands initiated transcriptional control in the tarxet cells.(2-1) all inhibited mveloid and erythroid differentiation.(2-2) Expression level of various HTF was changed by the differentiation stimulation and such changes were not modified by aN1 in all the HTF except for GATA2. The expression level of GATA2 was decreased when wild-type 32D cells differentiate responding to G-CSF, while it was maintained when aN1 was introduced into 32D (aN1/32D). Further exogenous expression of DN-GATA or PU.1, which is known to block the function of GATA factors, reverted the aN1-induced differentiation block. These results indicated that aN1 blocks differentiation of hematopoietic cells through sustaining the expression level and function of GATA2.[Conclusion] We revealed a part of mechanisms of initiation of Notch signaling. Activation of Notch blocks differentiation of hematopoietic cells, through sustaining the expression level and function of GATA2. Less

[目的]研究是如何生成Notch受体的信号，并且使用Notch2研究了Notcule的造血细胞中的NotiTi机制，检查了造血转录因子（HTF）的表达变化和造血细胞的生长。将Notch2分子的亚基裂解（1-2）。除GATA2外，在所有HTF中未经AN1的修饰均降低了野生型32D细胞对G-CSF INED的反应均引入32D（AN1/32D）（AN1/32D）。已知的是GATA因子的功能，AN1诱导的分化是通过造血细胞的分化

项目成果

Shimizu K: "Mouse Jagged1 physically interacts with Notch2 and other Notch receptors : assessment by quantitative methods."J Biol Chem. 274. 32961-32969 (1999)

Shimizu K：“小鼠 Jagged1 与 Notch2 和其他 Notch 受体发生物理相互作用：通过定量方法进行评估。”J Biol Chem。

Shimizu K, Chiba S, Saito T, Kumano K, Hirai H.: "Physical interaction of Delta1, Jagged1 and Jagged2 with Notch1 and Notch3 receptors"Biophys Biochem Res Commun. 276. 385-389 (2000)

Shimizu K、Chiba S、Saito T、Kumano K、Hirai H.：“Delta1、Jagged1 和 Jagged2 与 Notch1 和 Notch3 受体的物理相互作用”Biophys Biochem Res Commun。

Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T, Kanda Y, Hamada Y, Yazaki Y, Hirai H.: "Mouse Jagged1 physically interacts with Notch2 and other Notch receptors : assessment by quantitative methods"J Biol Chem.. 274. 32961-32969 (1999)

Shimizu K、Chiba S、Kumano K、Hosoya N、Takahashi T、Kanda Y、Hamada Y、Yazaki Y、Hirai H.：“Mouse Jagged1 与 Notch2 和其他 Notch 受体发生物理相互作用：定量方法评估”J Biol Chem..

Shimizu K: "Physical interaction of Deltal, Jagged1 and Jagged2 with Notch1 and Notch3 receptors."Biochem.Biophys.Res.Commun.. 276. 385-389 (2000)

Shimizu K：“Delta、Jagged1 和 Jagged2 与 Notch1 和 Notch3 受体的物理相互作用。”Biochem.Biophys.Res.Commun.. 276. 385-389 (2000)

Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H.: "Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis"Oncogene. 20. 88-96 (2001)

Imai Y、Kurokawa M、Izutsu K、Hangaishi A、Takeuchi K、Maki K、Okawa S、Chiba S、Mitani K、Hirai H.：“急性髓性白血病中 Smad4 基因的突变及其在白血病发生中的功能意义”癌基因。