MOLECULAR GENETICS OF TOPOSOMES EUCARYOTES

这个项目是关于模式的分子基础。 胚胎发生过程中的形成。生成和维护 多细胞生物体的模式需要整合 四个基本功能：(一)细胞之间的机械连接，(二) 位置指导，(Iii)DNA复制的控制，和(Iv) 控制细胞的运动和形状。该项目提出，所有 这些功能中的一项被赋予了一个大型多功能 其中的大分子组装的拓扑体，一个大的 寡聚糖蛋白复合体，是细胞表面的组成部分 受托介导细胞黏附和表达位置 信息。中心思想是，拓扑体属于 细胞表面信号分子的一般类别，包括 众所周知，糖蛋白复合体是胰岛素的受体， 表皮生长因子和免疫系统的受体。 拓扑体与这些其他受体共享一个细胞外 识别蛋白质配基的结合域，除了 配基是不同分子上另一个拓扑体的同源部分 手机。拓扑体可能结合在一个完整的膜上 似乎高度保守的受体，并与 纤维连接蛋白受体。我们进一步假设该受体具有 胞质信号发生域，类似于EPG和 膜结合型原癌基因家族和一个结合位点 细胞骨架的组成部分。 拓扑体的概念将通过实验来检验 它的预测。已有的拓扑体基因的测序 为海胆和果蝇克隆将是重中之重。 其他实验的目的是用 接触部位的活动性及其与 单克隆抗体。这些结果将与 发育中胚胎的原位标记实验 位置代码。拓扑体参与细胞外信号转导 DNA复制信号将通过阻止接触进行测试 在分离的细胞中具有恢复DNA合成的配体的位置 海胆胚胎。拓扑体被认为是关键分子 因为他们第一次解释了 为什么在癌症中失去接触抑制、体位指导 (导致侵袭性)和细胞骨架秩序总是联系在一起的。

This project is concerned with the molecular basis of pattern formation in embryogenesis. The generation and maintenance of patterns in multicellular organisms requires the integration of four basic functions: (i) mechanical linkage between cells, (ii) positional guidance, (iii) control of DNA replication, and (iv) control of cell movement and shape. The project proposes that all of these functions are vested in one large multifunctional macromolecular assembly of which the toposome, a large oligomeric glycoprotein complex, is the cell surface component entrusted with mediating cell adhesion and expressing positional information. The central idea is that toposomes belongs to the general class of cell surface signal molecules that includes such well known glycoprotein complexes as the receptors for insulin, epidermal growth factor and receptors of the immune system. Toposomes share with these other receptors an extracellular binding domain recognizing a protein ligand, except that the ligand is the cognate portion of another toposome on a different cell. Toposomes are presumably bound to an integral membrane receptor that appears to be highly conserved and related to the fibronectin receptor. We further postulate that this receptor has a cytoplasmic signal generating domain, analogous to EPG and the family of membrane-bound proto-oncogenes, and a binding site for components of the cytoskeleton. The toposome concept will be tested by experiments that examine its predictions. Sequencing of the toposome genes that have been cloned for the sea urchin and Drosophila will have high priority. Other experiments are aimed at isolating peptides with the activity of the contact site and its characterization with monoclonal antibodies. These results will be combined with in situ labeling experiments of the developing embryo to deduce the positional code. involvement of toposomes in transduction of signals for DNA replication will be tested by blocking the contact site with ligands that restore DNA synthesis in dissociated cells of sea urchin embryos. Toposomes are thought to be key molecules in tumorigenesis because they would explain for the first time why in cancer loss of contact inhibition, positional guidance (leading to invasiveness) and cytoskeletal order are always linked.