Joint study on regulation of cell profferation by cytokines

细胞因子调控细胞增殖的联合研究

• 批准号: 07044230
• 负责人: ARAI Ken-ichi
• 金额: $ 7.87万
• 依托单位: 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: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07044230/
• 关键词: Growth factor; chrmosomal replication; Signal transduction; Cytokine; Growth factor receptor; Cell cycle; Transcription factor; T cell activation

In this collaborative project, we are studying on the mechanisms of induction of DNA replication, gene expression and other various cellular responses in growth factor-mediated proliferation and differentiation of mammalian cells.This year, we have obtained the following results.1) We have isolated a putative regulatory subunit for fission yeast Hsk1 kinase. Among several S.pombe clones encoding Hsk1-interacting molecules, Him1 (H__-sk1 i__-nteracting m__-olecule 1) forms a complex with Hsk1, stimulates its kinase activity and is specifically phosphorylated by Hsk1. him1^+ is essential for viability of fission yeast cells and its transcription is cell cycle-regulated, reaching maximum at the G1/S boundary, although it is not under the control of cdc10^+.2) We have also isolated a novel human cDNA,H37, encoding a huCdc7-interacting molecule. H37 and huCdc7, when coexpressed with huCdc7 in COS7 cells or in insect cells, forms a complex and the complex formation activates huCdc kinase, re … More sulting in extensive phosphorylation of both huCdc and H37. This indicates that H37 is a regulatory subunit for huCdc kinase. Microinjection of antibodies against H37 protein inhibited DNA synthesis in primary fibroblast cells, indicating that the function of H37-huCdc7 is required for S phase initiation.3) We have mapped replication origins in the GM-CSF/IL-3 locus of the human 5q region by using the competitive PCR method. Our preliminary results indicate the presence of an active replication origin near the inducible DNaseI-hypersensitive site within the intergenic region.4) We have mapped tyrosine residues of the cytoplasmic region of beta-chain of GM-CSF receptore whose phosphorylation is required for DNA replication, induction of early response genes, prevention of apoptosis, and so on.5) We have shown that dimerization of Jak2 alone can induce induction of c-myc, STAT5 activation and cytokine-independent proliferation.6) We have isolated novel clones whish are induced by cytokine stimulation of mutant GM-CSF receptors capable specifically of promoting proliferaton.6) Administration of human GM-CSF to human GM-CSF receptor transgenic mice stimulated myelopoiesis as well as erythropoiesis and megakaryopoiesis in mice. it also affected the development of natural killer cells in the transgenic mice. Less

在这个协作项目中，我们是DNA复制生长因子介导的增殖和哺乳动物细胞区分的机制。我们已经获得了以下结果编码HSK1相互作用的分子1 I __- nteracting m __-甲状腺素1）与HSK1形成复合物，刺激其激酶活性，并且是由HSK1特别磷酸化的。细胞循环的DARY，尽管它不受CDC10^+的控制。在原发性成纤维细胞中均具有HUCDC和H37的广泛磷酸化，表明S相启动需要H37-HUCDC7的功能。通过使用竞争性PCR方法，人类5q的座位。 5）我们已经表明，仅JAK2的二聚化可以诱导C-YC，STAT5激活和细胞因子 - 单独的增殖。6）我们已经通过孤立的新型克隆诱导了孤立的克隆。突变的GM-CSF受体的细胞因子能够促进增殖。6）人类GM-CSF对人的GM-CSF施用，作为ASIS和巨型小鼠小鼠小鼠小鼠的巨核

项目成果

Masai,H.& Arai,K.: "Dna-A dependent assembly of the ABC primosome at the A site,a single-stranded DNA hairpin containing a dnaA box" Eur.J.Biochem.230. 384-395 (1995)

马赛，H.

Itoh, T et al: "Definition of the role of tyrosine residues of the common β subunit regulating multiple signaling pathways of Granulocyto Macrophage-Colony Stimulating Factor recepter." Mol.Cell.Biol.(in press).

Itoh, T 等人：“常见 β 亚基酪氨酸残基调节粒细胞巨噬细胞集落刺激因子受体多种信号通路的作用的定义。”（正在出版）。

Masuda, E.S., Liu, J., Imamura, R., Imai, S., Arai, K.and Arai, N.: "Control of NFATx1 nuclear translocation by a calcineurin-regulated inhibitory domain." Mol.Cell.Biol.17,4. 2066-2075 (1997)

Masuda, E.S.、Liu, J.、Imamura, R.、Imai, S.、Arai, K. 和 Arai, N.：“钙调神经磷酸酶调节的抑制域控制 NFATx1 核易位。”

Ohtoshi,A.et al.: "Genetic interactions between CDC7 and CDC28 : growth inhibition of cdc 28-1N by cdc7 point mutants." Genes to Cell.1. 895-904

Ohtoshi,A.等人：“CDC7 和 CDC28 之间的遗传相互作用：cdc7 点突变体对 cdc 28-1N 的生长抑制。”

Muto,A.et al.: "The β subunit of human GM-CSF receptor forms a homodimer and is activated by association with the a subunit." J.Exp.Med.183. 1911-1916 (1996)

Muto,A.et al.：“人类 GM-CSF 受体的 β 亚基形成同型二聚体，并通过与 α 亚基结合而被激活。”J.Exp.Med.1911-1916 (1996)。