Pleiotropic functions of cytokines and STAT5

细胞因子和 STAT5 的多效性功能

• 批准号: 13470070
• 负责人: KITAMURA Toshio
• 金额: $ 7.55万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470070/
• 关键词: Cytokine; signal transduction; STAT5; IL-6; NFκB; macrophage; M1; NFKB; START5

We have been working on molecular mechanisms of the pleiotropic functions of cytokines using the constitutively active mutants of STAT5 (Onishi et al. Mol Cell Biol, 1998; Ariyoshi et al. J Biol Chem, 2000) which we identified by PCR-driven random mutagenesis followed by retrovirus-mediated expression screening. STAT5 is a transcription factor known to induce the expression of a variety of target genes. We previously demonstrated that STAT5 could induce proliferation, differentiation, and apoptosis in the same cells through induction of pim-1, p21 and SOCS1, respectively (Nosaka et al, EMBO J, 1999). We have now identified a novel mechanism by which the constitutively active STAT5 induced macrophage differentiation of M1 cells ; the active STAT5 induced macrophage differentiation via autocrine production of IL-6 (Kawashima et al. J Immunol, 2001). Interestingly, the promoter of the IL-6 gene does not contain the biding site of STAT5, and the induction of IL-6 by the active STAT5 was mediated through activation of NFkB. Now we are investigating the underlying molecular mechanism, and the preliminary results indicate that a secreted protein induced by STAT5 activation is responsible for IL-6 production (Nakamura et al. J Biol Chem, 2002). The identification of this secreted protein is now ongoing.

我们一直在使用STAT5的结构性活性突变体来研究细胞因子的多效性功能的分子机制(Onishi等人。Mol Cell Biol，1998；Ariyoshi et al.J Biol Chem，2000)，我们通过聚合酶链式反应驱动的随机突变和逆转录病毒介导的表达筛选对其进行了鉴定。Stat5是一种转录因子，可诱导多种靶基因的表达。我们先前证明，STAT5可以分别通过诱导Pim-1、p21和SOCS1诱导同一细胞的增殖、分化和凋亡(Nosaka等人，EMBO J，1999)。我们现在已经确定了一种新的机制，通过结构性活性的STAT5诱导M1细胞的巨噬细胞分化；活性的STAT5通过自分泌IL-6诱导巨噬细胞分化(Kawashima等人)。《免疫杂志》，2001)。有趣的是，IL-6基因的启动子不包含STAT5的结合部位，而激活的STAT5通过激活NFkB来诱导IL-6的产生。现在我们正在研究潜在的分子机制，初步结果表明，由STAT5激活诱导的一种分泌蛋白负责IL-6的产生(Nakamura等人)。J Biol Chem，2002)。对这种分泌蛋白的鉴定目前正在进行中。

项目成果

Yamashita, Y.: "Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase"J Biol Chem. 276. 39012-39020 (2001)

Yamashita, Y.：“Sak 丝氨酸-苏氨酸激酶充当 Tec 酪氨酸激酶的效应子”J Biol Chem。

Nosaka, T., Morita, S., Kitamura, H., Nakajima, H., Shibata, F., Morikawa, Y., Kataoka, Y., Ebihara, Y., Kawashima, T., Itoh, T., Ozaki, K., Senba, E., Tsuji, K., Makishima, F., Yoshida, N., and Kitamura, T.: "Mammalian Twisted Gastrulation Is Essential f

野坂，T.，森田，S.，北村，H.，中岛，H.，柴田，F.，森川，Y.，片冈，Y.，海老原，Y.，川岛，T.，伊藤，T.，

Frasor, J.: "Differential roles for Stat5α and Stat5β in prolactin stimulation of estrogen receptor a and b transcription."Molecular Endcrinol.. 15. 2172-2181 (2001)

Frasor, J.：“Stat5α 和 Stat5β 在催乳素刺激雌激素受体 a 和 b 转录中的不同作用。”分子内分泌学.. 15. 2172-2181 (2001)

Nakamura, T.: "Cytokine receptor common β subunit-mediated STAT5 activation confers NFκB activation through IκB-independent mechanism in a murine pro B cell line Ba/F3"J.Biol.Chem.. (in press).

Nakamura, T.：“细胞因子受体常见 β 亚基介导的 STAT5 激活通过小鼠 pro B 细胞系 Ba/F3 中的 IκB 独立机制赋予 NFκB 激活”J.Biol.Chem..（出版中）。

Komano, H.: "A new functional screening system for identification of DNA encoding a regulator of γ-cleavage"J. Biol. Chem.. 277. 39627-39633 (2002)

Komano, H.：“用于鉴定编码 γ-裂解调节剂的 DNA 的新功能筛选系统”J. Biol. 277. 39627-39633 (2002)