ISGF3 Transcription Factor Family in Cytokine Signaling

细胞因子信号转导中的 ISGF3 转录因子家族

• 批准号: 7179310
• 负责人: David E Levy
• 金额: $ 59.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179310
• 关键词: Achievement; Animal Cancer Model; Animals; Antibodies; Binding; Biochemical; Biochemical Genetics; Biological; Biological Process; Biology; C-terminal; Cancer Biology; Cell Cycle; Cells; Cellular biology; Characteristics; Collection; Competence; Complex; Cytokine Signaling; Cytoplasm; Data; Development; Diagnosis; Dimerization; Disease; Drug Delivery Systems; Embryonic Development; Family; Family member; Future; Gene Expression; Genetic Transcription; Goals; Immune; Inflammatory Response; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Molecular; Motivation; Normal Cell; Nuclear Translocation; Numbers; Oncogene Proteins; Pathway interactions; Play; Process; Proteins; Regulation; Research; Resources; Role; STAT protein; STAT1 gene; STAT3 gene; Signal Transduction; Standards of Weights and Measures; Stem cells; Stimulus; Therapeutic; Transactivation; Transducers; Tumor Suppressor Proteins; Tyrosine; Tyrosine Phosphorylation; activating transcription factor; animal tissue; base; extracellular; genetic regulatory protein; human disease; interferon-stimulated gene factor 3; mutant; novel; novel strategies; src Homology Region 2 Domain; tool; trophoblast; tumor; tumor progression

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.

描述（由申请人提供）：信号转导剂和转录激活剂（STAT）蛋白最初被表征为通过信号依赖性酪氨酸磷酸化激活的潜在转录因子。该家族的两个创始成员 STAT1 和 STATS 在遗传和生化方面相互作用，并已被证明在先天免疫和炎症反应中发挥作用。最近的证据还表明，STAT1 具有肿瘤抑制基因的特征，STAT3 具有癌基因的特征，这些蛋白质在癌症进展中发挥着重要但目前仍知之甚少的作用。大量研究已经充实了 JAK-STAT 通路的细节，证明了酪氨酸磷酸化、二聚化、核转位、DMA 结合和转录诱导的重要性，这些特征符合 STAT 蛋白最初假设的作为细胞外信号直接转导器的作用。虽然这一范式有助于解释 STAT 功能的许多方面，但新出现的数据表明 STAT1 和 3 的某些生物学功能独立于经典途径的一个或多个基石。我们建议探索 STAT 依赖性过程的分子机制和生物学后果，目前的 JAK-STAT 信号传导模型尚未完全解释这些过程。我们建议追求以下具体目标： 1. 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.表征细胞周期中STAT1和STATS的调节、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，包括单突变和双突变细胞和动物、组织特异性突变动物、癌症动物模型以及针对 STAT 蛋白的抗体和分子工具。该提案目标的实现将增进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 功能机制理解的重大差距，将进一步努力优化针对 STATS 的治疗策略，并将促进开发更好地诊断和治疗人类疾病的新策略。