The mechanism of granulopoiesis and leukemogenesis by the activation of Stat3

Stat3 激活导致粒细胞生成和白血病发生的机制

• 批准号: 15390302
• 负责人: SHIMODA Kazuya
• 金额: $ 7.94万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390302/
• 关键词: G-CSF; Stat3; C; EBP α; Granulopoiesis; ERK; SOCS3; EBPα; 好中球

The Jak-Stat pathway plays an essential role in cytokine signaling. G-CSF promotes granulopoiesis, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the IL-3 dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/DNStat3) proliferate in G-CSF without differentiation. Gene expression profile of G-CSF-stimulated cell lines revealed that the expression of C/EBP_α was up-regulated by the activation of Stat3. And activated Stat3 bound to C/EBP_α, leading to the enhancement of the transcription activity of C/EBP_α. Conditional expression of C/EBP_α in 32Dcl3/DNStat3 cells after G-CSF stimulation abolishes the G-CSF dependent cell proliferation and induces granulocytic differentiation. These results show that one of the major roles of Stat3 in G-CSF signaling pathway is to augment the function of C/EBP_α.The function of Stat3 in vivo was examined using the Stat3 conditional deficient mice. Mice deficient for Stat3 in hematopoietic cells show neutrocytosis, and G-CSF-induced proliferation of progenitor cells was observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3 null bone marrow cells displayed a significant activation of ERK1/2 under basal conditions, and it was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. Stat3 functions in vivo as a negative regulator of G-CSF signaling by inducing SOCS3 expression, and ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.

Jak-Stat 通路在细胞因子信号转导中发挥重要作用。 G-CSF 促进粒细胞生成，Stat3 是 G-CSF 激活的主要 Stat 蛋白。用 G-CSF 处理后，IL-3 依赖性细胞系 32D 克隆 3 (32Dcl3) 分化为中性粒细胞，表达显性失活 Stat3 (32Dcl3/DNStat3) 的 32Dcl3 细胞在 G-CSF 中增殖而不分化。 G-CSF刺激的细胞系的基因表达谱显示，C/EBP_α的表达通过Stat3的激活而上调。并激活与C/EBP_α结合的Stat3，导致C/EBP_α转录活性增强。 G-CSF刺激后32Dcl3/DNStat3细胞中C/EBP_α的条件表达消除了G-CSF依赖性细胞增殖并诱导粒细胞分化。这些结果表明Stat3在G-CSF信号通路中的主要作用之一是增强C/EBP_α的功能。使用Stat3条件缺陷小鼠检查Stat3的体内功能。造血细胞中缺乏 Stat3 的小鼠表现出中性细胞增多，并且在 Stat3 缺陷小鼠中观察到 G-CSF 诱导的祖细胞增殖。在 Stat3 缺陷小鼠的造血细胞中，观察到痕量的 SOCS3（粒细胞生成的负调节因子），并且 G-CSF 刺激不会诱导 SOCS3 表达。 Stat3 缺失的骨髓细胞在基础条件下表现出 ERK1/2 的显着激活，并且通过 G-CSF 刺激而增强和维持。此外，添加 MEK1 抑制剂后，Stat3 缺陷型骨髓细胞对 G-CSF 的增殖增强显着降低。 Stat3 在体内通过诱导 SOCS3 表达作为 G-CSF 信号传导的负调节因子，而 ERK 激活是诱导造血细胞响应 G-CSF 增殖的主要因素。

项目成果

Tyk2 interacts with and phosphorylates Rack-1, a WD motif containing protein.

Tyk2 与 Rack-1（一种含有 WD 基序的蛋白质）相互作用并使其磷酸化。

• 发表时间: 2004
• 期刊: J Immunol 173
• 作者: Haro T

Physical and functional interactions between Daxx and DNA methyltransferase1 associated protein, DMAP.

Daxx 和 DNA 甲基转移酶 1 相关蛋白 (DMAP) 之间的物理和功能相互作用。

• 发表时间: 2004
• 期刊: J Immunol 172
• 作者: Kamezaki K;Shimoda K;Numata A;Matsuda T;Nakayama K;Harada M;Muromoto R
• 通讯作者: Muromoto R

Seto Y, Nakajima H, Suto A, Shimoda K, et al.: "Enhanced Th2 Cell-mediated Allergic Inflammation in Tyk2-deficient Mice."Journal of Immunology. 170. 1077-1083 (2003)

Seto Y、Nakajima H、Suto A、Shimoda K 等人：“Tyk2 缺陷小鼠中 Th2 细胞介导的过敏性炎症增强。”免疫学杂志。

Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth.

干扰素的细胞内信号转导抑制造血祖细胞生长。

• 发表时间: 2003
• 期刊: Br J Haematol 123
• 作者: Kamezaki K;Shimoda K;Numata A;Matsuda T;Nakayama K;Harada M;Muromoto R;Muromoto R;Kamezaki K;Seto Y;Muromoto R;Kamezaki K;Kato K
• 通讯作者: Kato K

Transgenic Mice Overexpressing Murine Thrombopoietin Develop Myelofibosis and Osteosclerosis.

过度表达鼠类血小板生成素的转基因小鼠会出现骨髓纤维化和骨硬化。

• 期刊: Leukemia Research (印刷中)
• 作者: K;Sekine Y;Ouchi Y;Takei N;Minabe Y et al.;Kakumitsu H
• 通讯作者: Kakumitsu H