INVESTIGATIONS ON THE INTEGRATED BEHAVIOR OF MOLECULAR REGULATORY NETWORKS THAT C

分子调控网络综合行为研究

• 批准号: 6289180
• 负责人: KURT KOHN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289180
• 关键词: biological information processing; biological models; cell cycle; computer simulation; genetic regulation; intermolecular interaction; mathematical model; model design /development; protein tyrosine kinase

The richness and complexity of the molecular regulatory network governing cell proliferation requires a concise and unambiguous method of representation. It is becoming difficult or impossible to keep in mind all of the molecular interactions that may be pertinent to the planning and interpretation of experiments in a given area or to generating functional hypotheses. Difficulties arise especially because of the rich cross-connectivity among different signaling pathways that control cell proliferation and DNA repair. In order to utilize extant information optimally, a road map of the known or suspected molecular interactions would be useful, if not essential. Not only must the information itself be handy, but literature citations for the pertinent evidence must be readily accessible. Moreover, the molecular interaction maps must be in a form that allows frequent updating to accommodate corrections and new data. Molecular interaction maps must be able to cope with the complexities that extensive experimental work has revealed. A diagram convention was therefore devised that allows protein-protein interactions and protein modification states to be clearly represented and that can cope with highly complex systems. During the past year, comprehensive molecular interaction maps were completed of the G1/S cell cycle control network and its connections to DNA repair, replication, and transcription. These maps were published in the August, 1999 issue of Mol. Biol. Cell 10: 2703-2734, together with a presentation of the diagram conventions. Also included were an annotation list for the interactions depicted and reference citations. The map was also placed on our Laboratorys web site where it can be conveniently updated and is publicly accessible (http://discover.nci.nih.gov/kohnk/interaction maps.html). The 109 included mono-molecular species are listed in an alphabetical index which gives the map coordinates where each species can be found. Multimolecular species are depicted by means of a convention of arrowed lines that connect the monomolecular components. Another convention is used to depict the complexities of protein modifications, especially phosphorylations. Symbol conventions also are defined for enzymatic action, stimulation, and inhibition. Each of 194 molecular interactions is marked with a symbol that refers to an annotation list where salient facts and literature references can be found. The maps suggest that many of the components can function as large-scale multiprotein complexes which can assemble at sites of DNA replication, repair, or transcription. The unusual richness of interactions between the p53- MDM2 subsystem and most other subsystems is shown in detail.Work was recently begun on a new molecular interaction map which will extend the representation of cell proliferation control to include signaling from receptors on the cell surface. The symbol conventions were enriched to permit representation of molecular interactions at the plasma membrane, transport between intracellular compartments, and new complexities arising from the interconversions of the various phosphatidylinositol phosphates. Since the global representation of all known growth factor receptors is at this stage prohibitively complicated, the focus will be on signaling from the epidermal growth factor receptors, since we have for these the best molecular interaction data. - Cell Cycle Regulation, Cell Proliferation Control, Molecular Interaction Networks, Molecular interaction Maps, Epidermal Growth Factor Receptor Signaling, DNA Repair,

细胞增殖的分子调控网络的丰富性和复杂性需要一个简洁和明确的表示方法。要记住所有可能与特定领域实验的计划和解释或产生功能假设有关的分子相互作用，变得越来越困难或不可能。困难的出现特别是因为控制细胞增殖和DNA修复的不同信号通路之间存在丰富的交叉连接。为了最佳地利用现有信息，已知或疑似分子相互作用的路线图将是有用的，如果不是必需的。不仅信息本身必须方便，而且相关证据的文献引用也必须容易获得。此外，分子相互作用图必须以允许频繁更新的形式，以适应校正和新数据。分子相互作用图必须能够科普大量实验工作所揭示的复杂性。因此，设计了一种图表约定，可以清晰地表示蛋白质-蛋白质相互作用和蛋白质修饰状态，并且可以科普高度复杂的系统。在过去的一年中，完成了G1/S细胞周期控制网络及其与DNA修复，复制和转录的联系的全面分子相互作用图。这些地图发表在1999年8月出版的Mol. Cell 10：2703-2734，连同图惯例的呈现。还包括所描述的相互作用和参考文献的注释列表。该地图还放在我们的图书馆网站上，方便更新，并向公众开放（http：discover.nci.nih.gov/kohnk/interaction maps.html）。所包括的109个单分子物种以字母索引的形式列出，该索引给出了每个物种可以找到的地图坐标。多分子物种通过连接单分子组分的箭头线的约定来描述。另一个惯例是用来描述蛋白质修饰的复杂性，特别是磷酸化。符号惯例也被定义为酶的作用，刺激和抑制。194种分子相互作用中的每一种都用一个符号标记，该符号指的是一个注释列表，在该列表中可以找到显著的事实和参考文献。这些地图表明，许多组分可以作为大规模的多蛋白质复合物发挥作用，这些复合物可以在DNA复制、修复或转录的位点组装。p53-MDM 2子系统和大多数其他子系统之间的相互作用的不寻常的丰富性显示在details.Work最近开始在一个新的分子相互作用的地图，这将扩大代表细胞增殖控制，包括从细胞表面上的受体的信号。丰富的符号约定，允许代表分子在质膜上的相互作用，细胞内室之间的运输，以及各种磷脂酰肌醇磷酸盐的相互转化所产生的新的复杂性。由于所有已知的生长因子受体的全球代表性在这个阶段是非常复杂的，重点将是从表皮生长因子受体的信号，因为我们有这些最好的分子相互作用的数据。- 细胞周期调控，细胞增殖控制，分子相互作用网络，分子相互作用图谱，表皮生长因子受体信号转导，DNA修复，