Molecular basis of cancer diathesis

为了开发新的策略来抑制癌症发生和控制癌症进展，在分子水平上理解原癌基因和抑癌基因产物的基本作用和调控特征是至关重要的。在这项研究中，我们广泛分析了src家族的原癌基因产物（SFK）的正常功能和调节，以了解SFK在癌症进展中所起的作用，特别是在转移活性的获得中。对缺乏Csk（SFK的负调节剂）的上皮癌细胞和突变小鼠的研究表明，SFK在细胞迁移和调节上皮样细胞向间质样细胞转变（EMT）中起关键作用。还发现SFK参与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Corpine及其相关分子 ...更多信息 在上皮样细胞向间质样细胞的转化中，细胞被鉴定为SFK的潜在靶点。此外，Csk作为这些现象的关键调节剂，这表明Csk可用作控制癌症进展和/或转移的潜在治疗靶点。2.在脂筏部分，提供了一个平台SFK信号，我们确定了一种新的膜磷蛋白Cbp（Csk结合蛋白）作为SFK的初始目标，并表明它作为膜支架蛋白Csk。3.为了分析SFK在动物中的基本作用，我们在C.优雅突变蠕虫的分析表明，SRC-1，Src的直向同源物，在器官发生过程中控制特定细胞类型的迁移中起着至关重要的作用。Rac信号通路被鉴定为SRC-1的下游靶标。4.基于Csk晶体结构提供的结构信息，我们提出了Csk调控SFK的分子基础。少

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