GENE ACTIVATION BY POLYPEPTIDES--CELL SURFACE TO NUCLEUS

胚胎发生过程中的许多发育事件和调控事件， 成年人依赖于细胞外信号多肽的存在 （ESP）。 超过35种不同的ESP通过 一组称为STAT的潜在转录因子的激活，双重 功能蛋白质作为信号转导和激活剂， 转录。 一系列的生理事件至少在 STAT的一部分包括先天免疫，即对 入侵的细菌和病毒，适当的T细胞功能，特别是在 选择对入侵生物的免疫反应类型， 骨髓中的其他功能。发展事件，如适当的 乳腺组织中的上皮细胞发育和对 生长激素也依赖于这些蛋白质。 最后，适当增长 控制需要这些蛋白质的作用。 该项目具有 长期的核心目标是了解 STAT在改变转录速率中的核作用。我们将 完成我们早期对转录定义的研究 通过体内测试， 转录和细胞生物学测定每个引物的特异性。 与-COOH末端核苷酸特异性相互作用的蛋白质 Stat 1的一个域，该域已被证明在 已经检测到转录激活。 的识别 每一种与TAD相互作用的蛋白质， 通过肽含量或通过克隆先前的 未被识别的蛋白质将是主要的初始目标。 这些互动 蛋白质很可能包括可能特异性针对 STAT转录因子组。 体内和体外 这些Stat 1-β相互作用的作用的转录测定 然后将进行蛋白质。 泛函理论的研究 Stat 1、2和3相互作用蛋白的相互作用应提供 全面了解STAT蛋白如何改变基因转录 以诱导或维持与以下相关的特定表型特性： 许多细胞外信号多肽。

Many developmental events during embryogenesis and regulatory events in adults depend upon the presence of extracellular signalling polypeptides (ESPs). Over 35 different ESPs exert their immediate effect through the activation of a set of latent transcription factors called STATs, dual function proteins that serve as signal transducers and activators of transcription. The array of physiologic events controlled at least in part by the STATs include innate immunity, i.e. the initial response to invading bacteria and viruses, proper T cell function particularly in choosing the type of immune responses to invading organisms and many other functions in the bone marrow. Developmental events such as proper epithelial cell development in breast tissue and correct responses to growth hormone also depend on these proteins. Finally, proper growth control requires the action of these proteins. This project has the central long-term goal of understanding the molecular basis for the nuclear action of the STATs in changing transcription rates. We will complete our earlier studies on the definition of transcriptional activation domains, TADs, of Stats 1, 2 and 3 by testing in in vivo transcriptional and cell biologic assays the specificity of each TAD. Proteins that are specifically interactive with the -COOH terminal TAD of Stat1, a domain already demonstrated to be required in transcriptional activation have been detected. The identification of each of these TAD-interactive proteins through mass spectrographic identification by peptide content or by cloning genes of previously unrecognized proteins will be a major initial goal. These interactive proteins very likely include co-activators that may be specific for the STAT group of transcription factors. In vivo and in vitro transcriptional assays of the role of these Stat1-TAD interactive proteins will then be carried out. The studies of functional interaction of the Stat 1, 2 and 3 interactive proteins should provide comprehensive insight into how STAT proteins change gene transcription to induce or maintain the specific phenotypic properties associated with the many extracellular signalling polypeptides.