GENE ACTIVATION BY POLYPEPTIDES--CELL SURFACE TO NUCLEUS

胚胎发生过程中的许多发育事件和成体中的调节事件取决于 细胞外信号多肽（ESP）的存在。超过35种不同的ESP发挥他们的即时 通过激活一组称为STAT的潜在转录因子，即双功能蛋白质， 作为信号转导子和转录激活子。一系列的生理事件 至少部分由STAT控制的免疫应答包括先天免疫，即对入侵的初始应答， 细菌和病毒，适当的T细胞功能，特别是在选择类型的免疫反应， 入侵生物和骨髓中的许多其他功能。发展事件，如适当的 乳腺组织中上皮细胞的发育和对生长激素的正确反应也取决于 这些蛋白质。最后，适当的生长控制需要这些蛋白质的作用。这个项目 中心的长期目标是了解STAT核作用的分子基础， 改变转录速率我们将完成我们早期对转录的定义的研究 通过在体内转录和细胞生物学中测试， 分析每一种酶的特异性。与-COOH末端特异性相互作用的蛋白质 已经证明在转录激活中需要的结构域Statl的结构域已经被发现。 检测到通过质谱鉴定这些TAD相互作用蛋白中的每一种 通过肽含量或通过克隆以前未识别的蛋白质的基因来鉴定将是主要的 初始目标。这些相互作用的蛋白质很可能包括可能特异性针对蛋白质的共激活物。 STAT组的转录因子，在体内和体外转录测定这些作用 然后将进行失速相互作用蛋白质。国家职能互动研究 1、2和3相互作用蛋白应提供STAT蛋白如何变化的全面见解 基因转录，以诱导或维持与许多 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 sjgnal 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 Statl, 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 Stall-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.