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，并且细胞在细胞因子耗尽时经历凋亡。由于我们已经证明了细胞因子刺激激活的RAS对于预防细胞死亡是重要的，我们通过使用RAS突变体分析了RAS下游的信号。我们发现，RAF/MAP激酶和由RAS激活的PI 3激酶都参与抑制细胞死亡。在没有细胞因子的情况下，半胱天冬酶-3被激活并参与诱导细胞死亡。此外，由于我们以前分离出的肿瘤抑制素M（OSM）作为一个精氨酸诱导的基因，我们寻找其生物活性。OSM被发现在AGM区域表达，并且显示出对造血细胞以及 ** 上皮细胞的发育具有深远的影响，可能作用于它们共同的前体细胞成血管细胞。利用AGM区的体外培养系统，研究了c-myb和AML在造血中的作用。OSM也被发现是发育中的支持细胞的生长因子。OSM受体的分子结构通过克隆受体cDNA来阐明。

项目成果

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。”

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。

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。”

Ohta,T.et al: "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.等人：“造血细胞细胞因子剥夺后细胞凋亡需要 caspase-3/CPP32 蛋白酶级联反应。”

Tanaka,M.et al.: "Reconstitution of the functional mouse oncostatin M(OSM)receptor:molecular cloning of the mouse OSM receptor b subunit." Blood. 93. 804-815 (1999)

Tanaka,M.et al.：“功能性小鼠制瘤素 M(OSM) 受体的重建：小鼠 OSM 受体 b 亚基的分子克隆。”