ISGF3 Transcription Factor Family in Cytokine Signaling

描述（由申请人提供）：信号转导和转录激活因子（STAT）蛋白最初被描述为由信号依赖性酪氨酸磷酸化激活的潜在转录因子。这个家族的两个创始成员，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中起作用。最近的证据还表明，STAT1具有肿瘤抑制因子的特征，而STAT3具有致癌基因的特征，这些蛋白在癌症进展中发挥着重要的作用，但迄今为止知之甚少。大量的研究已经充实了JAK-STAT通路的细节，证明了酪氨酸磷酸化、二聚化、核易位、DMA结合和转录诱导的重要性，这些特征符合STAT蛋白作为细胞外信号直接转导的最初假设的作用。虽然这种模式已经解释了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典型途径的一个或多个基础。我们建议探索目前JAK-STAT信号传导模型尚未完全解释的stat依赖过程的分子机制和生物学后果。我们提出以下具体目标：描述STATS在滋养外胚层功能和胚胎发育中的重要作用。2. 描述STATS在ras诱导的癌症中的作用。3. 描述STAT1和STATS在细胞周期中的调控、相互作用和功能。我们广泛收集的遗传和生化资源将促进这项研究，包括单和双突变细胞和动物，组织特异性突变动物，癌症动物模型，抗体和STAT蛋白特异性分子工具。本研究的目标的实现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功能机制的理解的主要差距，将进一步努力优化针对STATS的治疗策略，并将促进开发新的策略，以更好地诊断和治疗人类疾病。

DESCRIPTION (provided by applicant): 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 propose 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.