RHO PROTEINS AND MASS SPECTROMETRY

RHO 蛋白质和质谱法

• 批准号: 8168766
• 负责人: JEFFREY R PETERSON
• 金额: $ 0.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-10 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168766
• 关键词: Binding; Biological; Biology; Cell Cycle Progression; Cell Polarity; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Sequence Rearrangement; Disease; Drug Industry; Enzymes; Family; Funding; GTP-Binding Proteins; Genetic Transcription; Goals; Grant; Guanosine Triphosphate; Institution; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular Conformation; Neoplasm Metastasis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Proteins; Research; Research Personnel; Resources; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Protein; Source; United States National Institutes of Health; high throughput screening; human disease; inhibitor/antagonist; interest; loss of function; novel therapeutics; response; rho; small molecule; tool; tumorigenesis; web site

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Like Ras, the Rho family of small GTP-binding proteins contributes to tumorigenesis and metastasis through the activation of downstream effector proteins. In response to diverse upstream signals, Rho proteins exchange bound GDP for GTP and can then bind and activate a very large and functionally diverse set of effectors including enzymes and scaffolding proteins. These effectors mediate complex cellular responses including cell cycle progression, cytoskeletal rearrangements, cell polarity, and gene transcription but how they contribute to the cancer phenotype is largely unknown. Our long-term goal is to provide a comprehensive and quantitative description of the signaling pathways operating through the Rho proteins and to understand the biological importance of these pathways, how they are regulated, and how they are corrupted in human diseases. One major approach we are using to elucidate the functions of particular effectors is the identification of small-molecule inhibitors for specific effectors through high-throughput screening. These drug-like molecules are then used to reveal the consequence of protein loss of function, as small-molecule inhibitors are powerful tools to explore the biology of highly dynamic signaling pathways (Peterson and Mitchison, Chem. Biol., 9: 1275, 2002). In addition, these compounds may represent leads for novel therapeutics. Since many Rho family effectors are regulated by autoinhibition, we are particularly interested in compounds that inhibit effectors by allosterically stabilizing their native, autoinhibited conformation. We have proposed that this strategy could be used to develop highly specific inhibitors of a large class of signaling proteins that play central roles in cancer in other diseases but that have been largely ignored by the pharmaceutical industry (Peterson and Golemis, J. Cell. Biochem., 93: 68, 2004)--from Peterson Web Site.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 像RAS一样，小型GTP结合蛋白的Rho家族通过激活下游效应蛋白的激活有助于肿瘤发生和转移。为了响应各种上游信号，RHO蛋白质交换GDP的GDP与GTP结合，然后可以结合并激活一组非常大的效应子集，包括酶和脚手架蛋白。这些效应子介导了复杂的细胞反应，包括细胞周期进展，细胞骨架重排，细胞极性和基因转录，但是它们如何对癌症表型做出贡献是未知的。我们的长期目标是对通过Rho蛋白运行的信号通路提供全面和定量的描述，并了解这些途径的生物学重要性，如何调节以及如何在人类疾病中腐败。我们正在使用一种主要的方法来阐明特定效应子的功能是通过高通量筛选鉴定特定效应子的小分子抑制剂。然后，这些药物样分子被用来揭示蛋白质功能丧失的结果，因为小分子抑制剂是探索高度动态信号通路的生物学的强大工具（Peterson和Mitchison，Chem。Biol。，9：1275，2002）。此外，这些化合物可能代表新型治疗剂的铅。由于许多RHO家庭效应子受自身抑制的调节，因此我们对通过变构稳定其本地自身抑制构象来抑制效应子的化合物特别感兴趣。我们已经提出，该策略可用于开发高度特异性的抑制剂的大量信号传导蛋白，这些蛋白在其他疾病中在癌症中起着核心作用，但在药物行业很大程度上忽略了这些蛋白质（Peterson和Golemis，J。Cell。Biochem。，93：68，2004）。