サイトカインによる細胞の増殖分化と細胞死のシグナル伝達

细胞因子对细胞增殖分化和细胞死亡的信号转导

• 批准号: 09044264
• 负责人: MIYAJIMA Atsushi
• 金额: $ 3.52万
• 依托单位: Institute of Molecular and Cellular Biosciences, The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044264/
• 关键词: cytokine; cytokine receptors; signal transduction; apoptosis; hematopoiesis; germ cells; endothelial cells; development; オンコスタチンM; 血管内皮; セルトリ細胞; 始原生殖細胞; 細胞増殖; 細胞分化; 細胞死; 白血病

Survival of hematopoietic cells depends on cytokine signals and cells undergo apoptosis upon cytokine depletion. As we have already demonstrated that RAS activated by cytokine stimulation is important for prevention of cell death, we analyzed signals downstream of RAS by using RAS mutants. We found that both RAF/MAP kinase and PI3 kinase activated by RAS are involved in suppression of cell death. In the absence of cytokines, caspase-3 is activated and is involved in induction of cell death. In addition, as we previously isolated Oncostatin M (OSM) as a cytokine-inducible gene, we searched for its biological activity. OSM was found to be expressed in the AGM region and was shown to have a profound effect on the development of hematopoietic cells as well as **dothelial cells, possibly acting on their common precursor cells, hemangioblasts. Using the in vitro culture system of the AGM region, role of c-myb and AML in hematopoiesis was studied. OSM was also found to be a growth factor of developing sertoli cells. The molecular structure of the OSM receptor was elucidated by cloning of the receptor cDNA.

造血细胞的存活取决于细胞因子信号，细胞因子耗尽后细胞会发生凋亡。正如我们已经证明细胞因子刺激激活的 RAS 对于预防细胞死亡很重要，我们通过使用 RAS 突变体分析了 RAS 下游的信号。我们发现 RAS 激活的 RAF/MAP 激酶和 PI3 激酶都参与抑制细胞死亡。在没有细胞因子的情况下，caspase-3 被激活并参与诱导细胞死亡。此外，由于我们之前分离出制瘤素M（OSM）作为细胞因子诱导基因，因此我们寻找其生物活性。 OSM被发现在AGM区域表达，并被证明对造血细胞和**细胞的发育有深远的影响，可能作用于它们的共同前体细胞，成血管细胞。利用AGM区域的体外培养系统，研究了c-myb和AML在造血中的作用。 OSM 还被发现是发育支持细胞的生长因子。通过克隆受体cDNA阐明了OSM受体的分子结构。

项目成果

Hara, T., K.Tamura, Y.Mukouyama, H.J Kim, H.Kogo, P.J.Donovan and A.Miyajima: "Distinct roles of oncostatin M and leukemia inhibitory factor for the development of germ cells and testis." Develop.Biol.201. 144-153 (1998)

Hara, T., K.Tamura, Y.Mukouyama, H.J Kim, H.Kogo, P.J.Donovan 和 A.Miyajima：“制瘤素 M 和白血病抑制因子对生殖细胞和睾丸发育的独特作用。”

Kurihara R.et al.: "Regulation of crytokine-mediated cell survival through two distinct pathways, Ras/NFIL3 (E4BP4) and Bcl-XL/Caspase-3, in murine IL-3 dependnet pro-B lymphocytes" Mol. Cell. Biol. in press. (1999)

Kurihara R. 等人：“在鼠 IL-3 依赖性亲 B 淋巴细胞中，通过 Ras/NFIL3 (E4BP4) 和 Bcl-XL/Caspase-3 两种不同途径调节隐因子介导的细胞存活”Mol。

Mukouyama, Y.et al.: "In vitro expansion of murine hematopoietic progenitors derived from the embryonic aorta gonad mesonephros region." immunity. 8. 105-114 (1998)

Mukouyama，Y.et al.：“来自胚胎主动脉性腺中肾区域的小鼠造血祖细胞的体外扩增。”

Ohta, T., T.Kinoshita, M.Naito, M.Masutani, T.Tsuruo and A.Miyajima: "Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells." J.Biol.Chem. 272. 23111-23116 (1997)

Ohta, T.、T.Kinoshita、M.Naito、M.Masutani、T.Tsuruo 和 A.Miyajima：“造血细胞细胞因子剥夺后细胞凋亡死亡需要 caspase-3/CPP32 蛋白酶级联反应。”

Mukouyama, Y., T.Hara, M.J.Xu, K.Tamura, P.J.Donovan, H.Kogo, K.Tsuji, T.Nakahata, and A.Miyajima: "In vitro expansion of murine hematopoietic progenitors derived from the embryonic aorta gonad mesonephros region." Immunity. 8. 105-114 (1998)

Mukouyama，Y.，T.Hara，M.J.Xu，K.Tamura，P.J.Donovan，H.Kogo，K.Tsuji，T.Nakahata 和 A.Miyajima：“来自胚胎主动脉性腺的小鼠造血祖细胞的体外扩增