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

• 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

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的生长、分化和恶性转化的机制，得到如下结果：1.造血细胞的生长、分化和恶性转化的机制。野生型KIT和致癌型（Asp814Val） KIT均通过酪氨酸719.2激活PI3-K信号通路诱导细胞生长。野生型KIT通过Tyrosine719和Tyrosine567.3激活Src家族酪氨酸激酶和PI3-K介导趋化作用。含有ITD的致癌FLT3可增强介导细胞生长的Pim-2的表达，同时抑制诱导粒细胞分化的PU.1和c/EBPa的表达，从而促进未成熟髓细胞的生长，抑制其分化。Ras、STAT5和PI3-K三者之间的功能协同是BCR/ABL癌基因充分发挥致瘤活性的必要条件。PML抑制STAT3活性，而其致癌形式PML/RARa则增强其活性。E2F1是Gl/S转变的关键调节因子，通过特异性抑制NF-kB活性使宿主细胞对Gl/S转变敏感。我们克隆了一个新的抗凋亡分子Anamorsin，它与已知的凋亡相关分子没有同源性。由于最终造血功能的缺陷，Anamorsin基因敲除小鼠在妊娠后期是胚胎致死的。

项目成果

Ezoe, S., Matsumura, I., Gale, K., Ishihara, K., Minegishi, N., Machii, T., Kitamura, T.Yamamoto, M., Enver, T., Kanakura, Y.: "GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoiesis through accumulation of p21^<WAF1> and p2

Ezoe, S.、Matsumura, I.、Gale, K.、Ishihara, K.、Minegishi, N.、Machii, T.、Kitamura, T.Yamamoto, M.、Enver, T.、Kanakura, Y.：“

Matsumura, I. et al.: "Cell cycle regulation in hematopoietic stem cells."Res.Adv.in Blood. 2. 39-49 (2003)

Matsumura, I. 等人：“造血干细胞的细胞周期调节。”Res.Adv.in Blood。

Matsumura I, et al.: "Roles for E2F1 and c-Myc in the regulation of cell growth and survival"Cell Cycle. 2. 333-338 (2003)

Matsumura I 等人：“E2F1 和 c-Myc 在细胞生长和存活调节中的作用”细胞周期。

Tanaka S, et al.: "Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome"Int.J.Mol.Med.. 12. 225-230 (2003)

Tanaka S，等：“慢性疲劳综合征中针对毒蕈碱胆碱能受体的自身抗体”Int.J.Mol.Med..12.225-230(2003)

Shibayama, H., Takai, E., Matsumura, I., Kouno, M., Morii, E., Kitamura, Y, Takeda,.JV, Kanakura, Y.: "Identification of a cytokine-induced antiapoptotic molecule Anamorsin essential for definitive hematopoiesis."J.Exp.Med.. 199. 581-592 (2004)

Shibayama, H.、Takai, E.、Matsumura, I.、Kouno, M.、Morii, E.、Kitamura, Y、Takeda,.JV、Kanakura, Y.：“细胞因子诱导的抗凋亡分子 Anamorsin 的鉴定