Molecular basis of cancer diathesis

癌症素质的分子基础

• 批准号: 14032201
• 负责人: OKADA Masato
• 金额: $ 60.22万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14032201/
• 关键词: oncogene; cancer; tyrosine kinase; signal transduction; epithelia; Src; Csk; Rafts; 浸潤転移; 上皮組織; 細胞接着; 線虫; 遺伝子; 癌; 酵素; 発生・分化; SFK; Cbp

To develop new strategies to suppress carcinogenesis and to control cancer progression, it is critical to understand the fundamental roles and regulatory features of proto-oncogene and anti-oncogene products at the molecular level. In this study, we extensively analyzed the normal functions and regulation of the src family of proto-oncogene products (SFK) in order to understand the role played by SFK in cancer progression, and particularly in the acquisition of metastatic activity.1. Studies of epithelial cancer cells and mutant mice that lack Csk, a negative regulator of SFK, revealed that SFK plays critical roles in cell migration and in the regulation of the epithelial-like cell to mesencymal-like cell transition (EMT). It was also found that SFK is involved in the cell-cell adhesion required for the maintenance of cell polarity and for the regulation of cell proliferation through the control of cytoskeletal organization. Cortactin, an actin binding protein, and its associated molec … More ules were identified as potential targets of SFK in the epithelial-like cell to mesencymal-like cell transition. Furthermore, Csk acted as the critical regulator of these phenomena, suggesting that Csk could be used as a potential therapeutic target to control cancer progression and/or metastasis. 2. In the lipid raft fraction that provides a platform for SFK signaling, we identified a novel membrane phosphoprotein Cbp (Csk binding protein) as an initial target of SFK, and showed that it serves as a membrane scaffold protein for Csk. 3. To analyze the fundamental roles of SFK in animals, we identified SFK and Csk orthologues in C. elegans. Analysis of mutant worms revealed that SRC-1, an orthologue of Src, plays an essential role in controlling the migration of specific cell types during organogenesis. The Rac signaling pathway was identified as a downstream target of SRC-1. 4. Based on the structural information provided by the crystal structure of Csk, we proposed a molecular basis for SFK regulation by Csk. Less

为了制定抑制癌变并控制癌症进展的新策略，了解原始癌基因和抗癌基因在分子水平上的基本作用和调节特征至关重要。在这项研究中，我们广泛分析了SRC家族的正常功能和调节原癌基因产品（SFK），以了解SFK在癌症进展中所起的作用，尤其是在转移性活动中所起的作用。1。对SFK的负调节剂缺乏CSK的上皮癌细胞和突变小鼠的研究表明，SFK在细胞迁移以及对上皮样细胞对介体样细胞转变（EMT）的调节中起关键作用。还发现SFK参与了维持细胞极性所需的细胞 - 细胞粘附，并通过控制细胞骨架组织来调节细胞增殖。肌动蛋白结合蛋白及其相关的分子……更多的ULE被鉴定为上皮样细胞中SFK的潜在靶标的肌动蛋白的结合蛋白。此外，CSK充当这些现象的关键调节剂，这表明CSK可以用作控制癌症进展和/或转移的潜在治疗靶标。 2。在为SFK信号提供平台的脂质筏部分中，我们确定了一种新型的膜磷酸蛋白CBP（CSK结合蛋白）为SFK的初始靶标，并表明它是CSK的膜支架蛋白。 3。为了分析SFK在动物中的基本作用，我们确定了秀丽隐杆线虫中的SFK和CSK直系同源物。对突变蠕虫的分析表明，SRC-1（SRC的直系同源物）在控制器官发生过程中特定细胞类型的迁移中起着至关重要的作用。 RAC信号通路被确定为SRC-1的下游目标。 4。基于CSK晶体结构提供的结构信息，我们提出了CSK调节SFK调控的分子基础。较少的

项目成果

Shimizu, K.: "SCOP, a novel binding partner of K-Ras in the membrane rafts, negatively regulates MAPK pathway"J. Biol. Chem.. (in press). (2003)

Shimizu, K.：“SCOP 是膜筏中 K-Ras 的一种新型结合伴侣，对 MAPK 通路具有负调节作用”J.

Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG.

• DOI: 10.1083/jcb.200401093
• 发表时间: 2004-08-02
• 期刊: The Journal of cell biology
• 作者: Fukuhara T;Shimizu K;Kawakatsu T;Fukuyama T;Minami Y;Honda T;Hoshino T;Yamada T;Ogita H;Okada M;Takai Y
• 通讯作者: Takai Y

Mechanism of Csk-mediated down regulation of Src family tyrosine kinases in EGF signaling.

EGF 信号传导中 Csk 介导的 Src 家族酪氨酸激酶下调机制。

• 发表时间: 2004
• 期刊: J.Biol.Chem. 279
• 作者: Mimuro;M.;H.Kikuchi;Matsuoka H
• 通讯作者: Matsuoka H

Csk regulates integrin-mediated signals : involvement of differential activation of ERK and Akt.

Csk 调节整合素介导的信号：参与 ERK 和 Akt 的差异激活。

• 发表时间: 2003
• 期刊: Biochem Biophys Res Commun. 303
• 作者: Gu;J.
• 通讯作者: J.

Kono, H.: "Spatial raft coalescence represents an initial step in Fc gamma R signaling"J. Immunol.. 169. 193-203 (2002)

Kono, H.：“空间筏合并代表 Fc gamma R 信号传导的第一步”J.