MOLECULAR GENETICS OF TOPOSOMES EUCARYOTES

这个项目是关于模式的分子基础 在胚胎发生中形成。 的产生和维持 多细胞生物中的模式需要整合 四个基本功能：（i）细胞之间的机械连接，（ii） 位置指导，（iii）DNA复制的控制，和（iv） 控制细胞的运动和形状。 该项目建议，所有 这些功能属于一个大型多功能 大分子组装体， 寡聚糖蛋白复合物，是细胞表面成分 被委托介导细胞粘附和表达位置 信息. 其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 作为胰岛素受体的众所周知的糖蛋白复合物， 表皮生长因子和免疫系统受体。 拓扑体与这些其他受体共享一个细胞外 识别蛋白质配体的结合结构域，除了 配体是另一个拓扑体的同源部分， cell. 拓扑体被认为是结合在一个完整的膜上 受体，似乎是高度保守的，并与 纤连蛋白受体 我们进一步假设，这种受体具有 - 胞质信号产生结构域，类似于EPG， 膜结合的原癌基因家族，以及 细胞骨架的组成部分。 拓扑体的概念将通过实验来检验， 其预测。 对已经被发现的拓扑体基因进行测序 海胆和果蝇的克隆将具有高度优先权。 其他实验旨在用所述肽分离肽。 接触部位的活性及其表征， 克隆抗体 这些结果将结合在 发育中胚胎的原位标记实验，以推断 位置码 拓扑体参与 DNA复制的信号将通过阻断接触来测试 与配体的位点，其恢复分离的细胞中的DNA合成， 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了接触抑制， （导致侵入性）和细胞骨架顺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.