Investigations on the integrated behavior of molecular regulatory networks that

分子调控网络整合行为的研究

• 批准号: 6433077
• 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/6433077
• 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 previous 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 Laboratory's web site where it can be conveniently updated and is publicly accessible (http://discover.nci.nih.gov/kohnk/interaction_maps.html). The monomolecular 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 interaction is marked with a symbol that refers to an annotation list where salient facts and literature references can be found. During the current year, the mapping conventions were extended so as to accommodate (1) intramolecular controls (e.g. Src), (2) events at the plasma membrane (e.g. interactions involving the EGF receptor family), (3) gene regulation events (e.g. the complex controls on E2F-dependent gene expression), and (4) controls involving phosphoinositides (e.g. involving PI-3-kinase, PTEN, and Akt/PKB). Preliminary molecular interaction maps of these networks have been prepared and relevant recent literature has been collected and organized. A formal version of the extended mapping conventions has been submitted for publication, together with illustrative versions of the essentials of the above interaction maps. Interaction maps and associated annotations have also been prepared for controls of apoptosis, including the subsystems centered (1) at mitochondris, (2) at TNF/Fas receptors at the plasma membrane, and (3) at effector caspases. A map also underway centers on the control of beta-catenin, involving E-cadherin, APC, GSK-beta, Axin, as well as inputs from Wnt. The mapping efforts were focused on systems that are often defective in common types of human cancer. Understanding of the functional consequences of these defects is a basis upon which new targeted therapies can be directed. Molecular interaction maps will help to guide these endeavors.

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。 该地图还放在我们实验室的网站上，可以方便地更新并向公众开放（http：//www.nci.nih.gov/kohnk/interaction_maps.html）。 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。 每个交互都用一个符号标记，该符号指向一个注释列表，在该列表中可以找到突出的事实和文献参考。 在本年度，映射惯例得到扩展，以适应（1）分子内控制（例如Src），（2）质膜事件（例如涉及EGF受体家族的相互作用），（3）基因调控事件（例如，对E2 F依赖性基因表达的复杂控制），和（4）涉及磷酸肌醇的控制（例如涉及PI-3-激酶、PTEN和Akt/PKB）。这些网络的初步分子相互作用的地图已经准备好，相关的最近的文献已经收集和组织。扩展映射约定的正式版本已提交出版，同时还提供了上述交互映射要点的说明版本。 相互作用图和相关注释也已准备用于细胞凋亡的控制，包括以（1）线粒体，（2）质膜上的TNF/Fas受体和（3）效应器半胱天冬酶为中心的子系统。 一个地图也正在进行中的控制β-连环蛋白，涉及E-钙粘蛋白，APC，GSK-β，轴蛋白，以及从Wnt的输入。 绘图工作的重点是在常见类型的人类癌症中经常有缺陷的系统。 对这些缺陷的功能后果的理解是新的靶向治疗可以指导的基础。 分子相互作用图将有助于指导这些努力。