ISGF3 Transcription Factor Family in Cytokine Signaling

信号转导和转录激活因子(STAT)蛋白最初的特征是 信号依赖的酪氨酸磷酸化激活的潜伏转录因子。两位创始成员 在这个家族中，STAT1和STATS在遗传和生化上相互作用，并已被证明在 先天免疫和炎症反应。最近的证据还表明，STAT1具有以下特征 肿瘤抑制因子和STAT3具有癌基因的特征，这些蛋白发挥着重要的作用，但作为 然而，人们对其在癌症进展中的作用知之甚少。 大量的研究已经充实了JAK-STAT途径的细节，证明了 酪氨酸磷酸化、二聚化、核转位、DMA结合和转录的重要性 诱导，符合STAT蛋白作为胞外直接转导分子的最初假定作用的特征 信号。虽然这一范例解释了STAT功能的许多方面，但新出现的数据表明 STAT1和STAT3的一些生物学功能独立于STAT1和STAT3的一个或多个基石 经典途径。我们致力于探索其分子机制和生物学后果。 JAK-STAT信号的当前模型不能完全解释的STAT依赖的过程。 我们建议追求以下具体目标： 1.鉴定STATS在滋养外胚层功能和胚胎发育中的重要作用。 2.研究STATS在RAS诱导的肿瘤中的作用。 3.研究STAT1和STATS在细胞周期中的调控、相互作用和功能。 这项研究将通过我们广泛收集的遗传和生化资源来促进， 包括单、双突变细胞和动物、组织特异性突变动物、 癌症，以及针对STAT蛋白的抗体和分子工具。实现本组织的目标 该提案将增加我们对这些蛋白质在正常生物学和癌症中的复杂作用的理解， 将弥合我们目前对STAT功能机制的理解上的一个重大差距，将进一步推动我们的 努力优化针对STATS的治疗策略，并将促进 更好地诊断和治疗人类疾病的新战略。

Signal Transducers and Activators of Transcription (STAT) proteins were originally characterized as latent transcription factors activated by signal-dependent tyrosine phosphorylation. Two founding members of this family, STAT1 and STATS, interact genetically and biochemically and have been shown to function in innate immune and inflammatory responses. Recent evidence also shows that STAT1 has characteristics of a tumor suppressor and STAT3 has characteristics of an oncogene, and these proteins play important but as yet poorly understood roles in cancer progression. A large body of research has fleshed out details of the JAK-STAT pathway, demonstrating the importance of tyrosine phosphorylation, dimerization, nuclear translocation, DMA binding, and transcription induction, features that fit the originally postulated role of STAT proteins as direct transducers of extracellular signals. While this paradigm has served to explain many aspects of STAT function, emerging data suggest that some biological functions of STAT1 and 3 are independent of one or more of the cornerstones of the canonical pathway.We proopse to explore the molecular mechanisms and biological consequences of STAT-dependent processes that are not fully explained by current models of JAK-STAT signaling. We propose to pursue the following specific aims: 1. Characterize the essential role of STATS in trophectoderm function and embryonic development. 2. Characterize the role of STATS in Ras-induced cancer. 3. Characterize the regulation, interaction, and function of STAT1 and STATS during the cell cycle. This research will be facilitated by our extensive collection of genetic and biochemical resources, including single and double mutant cells and animals, tissue-specific mutant animals, animal models of cancer, and antibody and molecular tools specific for STAT proteins. Achievement of the goals of this proposal will increase our understanding of the complex roles of these proteins in normal biology and cancer, will bridge a major gap in our current understanding of the mechanisms of STAT function, will further our efforts towards optimization of therapeutic strategies targeting STATS,and will facilitate development of novel strategies for better diagnosis and treatment of human disease.