GENE ACTIVATION BY POLYPEPTIDES--CELL SURFACE TO NUCLEUS

超出所提供的空间。胚胎发生过程中的许多发育事件和成人的调节事件取决于胞外信号多肽（ESP）的存在。超过35种不同的ESP通过激活一组称为STAT的潜在转录因子发挥其直接作用，STAT是充当信号转导子和转录激活子的双功能蛋白质。至少部分由STAT控制的一系列生理事件包括先天免疫，即对入侵细菌和病毒的初始应答，适当的T细胞功能，特别是在选择对入侵生物体的免疫应答类型方面，以及骨髓中的许多其他功能。发育事件，如乳腺组织中适当的上皮细胞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。该项目的中心长期目标是了解STAT在改变转录速率中的核作用的分子基础。我们将通过在体内转录和细胞生物学试验中测试每个转录因子的特异性，完成我们早期关于Stats 1，2和3的转录激活结构域（TAD）定义的研究。已经检测到与Statl的-COOH末端结合区特异性相互作用的蛋白质，Statl的-COOH末端结合区是已经证明在转录激活中需要的结构域。通过质谱鉴定肽含量或通过克隆以前未识别的蛋白质的基因来鉴定这些TAD相互作用蛋白质中的每一种将是主要的初始目标。这些相互作用蛋白很可能包括可能对STAT组转录因子具有特异性的共激活物，然后将进行这些Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall-Stall- STAT 1，2和3相互作用蛋白的功能相互作用的研究应该提供全面的洞察STAT蛋白如何改变基因转录，以诱导或维持与许多细胞外信号多肽相关的特定表型特性。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================