Analysis on the mechanism of survival, growth and differentiation of hematopoietic cells

造血细胞存活、生长和分化机制分析

基本信息

批准号：
14370302
负责人：
KANAKURA Yuzuru
金额：
$ 9.6万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370302/
关键词：
KIT FLT3 ROS E2F1 NF-kB apoptosis Anamorsin Bcl-XL NF-κB PML 増殖分化シグナル伝達 STAT3 転写因子白血病 RARα

项目摘要

In this study, we have analyzed the mechanisms of growth, differentiation and malignant transformation of hematopoietic cells from the aspects of signal transduction, transcriptional regulation, cell cycle regulation and apoptosis and got the results as follows :1.Both wild-type KIT and oncogenic (Asp814Val) KIT induce cell growth by activating PI3-K signal pathway through Tyrosine719.2.Wild type KIT mediates chemotaxis by activating Src family tyrosine kinases and PI3-K through Tyrosine719 and Tyrosine567.3.Oncogenic FLT3 containing the internal tandem duplication (ITD) enhances the expression of Pim-2 that mediates cell growth, while it suppresses that of PU.1 and c/EBPa, both of which induce granulocytic differentiation, thereby enhancing the growth and inhibiting the differentiation of immature myeloid cells.4.Functional cooperation among Ras, STAT5, and PI3-K is required for full oncogenic activity of BCR/ABL oncogene.5.PML inhibits STAT3 activity, while its oncogenic form PML/RARa enhances its activity.6.E2F1, a critical regulator of Gl/S transition, sensitizes host cells to apoptosis by inhibiting NF-kB activity specifically at Gl/S transition.7.We have cloned a novel anti-apoptotic molecule Anamorsin, which reveals no homology to known apoptosis related molecules.8.Knockout mice for Anamorsin are embryonic lethal at late gestation due to the defect of definitive hematopoiesis.

本研究从信号转导、转录调控、细胞周期调控和凋亡等方面分析了造血细胞生长、分化和恶变的机制，得到如下结果：1.野生型KIT和致癌型KIT (Asp814Val) KIT 通过酪氨酸719.2 激活 PI3-K 信号通路来诱导细胞生长。野生型 KIT 通过激活 Src 家族酪氨酸激酶和介导趋化性PI3-K 通过酪氨酸 719 和酪氨酸 567.3。含有内部串联重复 (ITD) 的致癌 FLT3 增强介导细胞生长的 Pim-2 的表达，同时抑制 PU.1 和 c/EBPa 的表达，两者均诱导粒细胞生长分化，从而促进未成熟髓系细胞的生长并抑制其分化。4.Ras、STAT5和PI3-K 是 BCR/ABL 癌基因完全致癌活性所必需的。5.PML 抑制 STAT3 活性，而其致癌形式 PML/RARa 增强其活性。6.E2F1 是 Gl/S 转变的关键调节因子，使宿主细胞对通过在 Gl/S 转换处特异性抑制 NF-kB 活性来抑制细胞凋亡。 7.我们克隆了一种新型抗凋亡分子 Anamorsin，它与已知的没有同源性8.阿那莫辛基因敲除小鼠由于终生造血功能缺陷，在妊娠晚期胚胎致死。