Transcriptional control mechanisms by ETS factors

ETS因子的转录控制机制

• 批准号: 7937169
• 负责人: Barbara J Graves
• 金额: $ 14.16万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937169
• 关键词: Abbreviations; Acetylation; Address; Affect; Amides; Amino Acids; Apoptosis; Binding; Biochemical; Biological; Biological Models; Biological Process; Calcium; Calcium Signaling; Cell Cycle Regulation; Cell Nucleus; Cells; Chemicals; DNA Binding; DNA Binding Domain; Development; Docking; EP300 gene; ETS Family Protein; Equilibrium; Event; Evolution; Family; Family member; Functional disorder; Gene Activation; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genomics; Glossary; Goals; Human; Hydrogen; Link; MAP Kinase Gene; MAPK1 gene; Malignant Neoplasms; Maps; Mediating; Modeling; Modification; Molecular; Molecular Conformation; Motion; Mutate; Mutation; Nuclear Magnetic Resonance; Pathway interactions; Phosphorylation; Positioning Attribute; Post-Translational Protein Processing; Property; Protein Dynamics; Proteins; Psychological reinforcement; RAS genes; Recruitment Activity; Regulation; Relaxation; Repression; Research; Research Personnel; Resolution; Role; Sampling; Serine; Signal Pathway; Signal Transduction; Site; Specificity; Staging; Testing; Transcriptional Regulation; Vertebral column; flexibility; in vitro testing; inorganic phosphate; insight; millisecond; paralogous gene; programs; promoter; protein function; quantum; tool; transcription factor

DESCRIPTION (provided by applicant): The long-term objectives of the proposed research are to understand how specificity is determined within a family of eukaryotic regulatory transcription factors. The ets gene family, which is found throughout the metazoa, has 27 human paralogs. ETS proteins have highly conserved DNA binding properties, yet display unique distinct biological properties. Thus, specificity must have evolved to direct these proteins to function in unique biological contexts. This proposal focuses on how signaling pathways affect the function of ETS proteins to give distinct activities. Aim I investigates the autoinhibition of Ets-1 DNA binding, including reinforcement by calciumdependent phosphorylation. Biochemical and biophysical approaches will test the role of protein dynamics and conformational change in the regulation of Ets-1 DNA binding. A phosphorylation-dependent rheostat model of Ets-1 regulation will be tested in vitro and in cells. Aim II investigates Ets-1 and highly-related Ets-2 as effectors of Ras/MAPKinase signaling. We will focus on the macromolecular interfaces that mediate the docking of the MAPK ERK2 to Ets-1 and Ets-2 and the phosphorylation-dependent recruitment of the co-activators CBP/p300. In addition, two recently discovered Ets-1 modifications, acetylation and sumolation, will be investigated. Aim III will identify authentic transcriptional targets for Ets-1 and Ets-2 to investigate how signaling impinges on the activity of Ets-1 and Ets-2 at genomic loci. We will test the role of post-translational modifications and factor assembly in gene activation and repression. Ras/MAPK signaling and the ETS family of transcription factors regulate genes necessary for control of the cell cycle, apoptosis, and normal differentiation. Mutation of human ras and ets genes contribute to cellular dysfunction in cancer. Indeed, the ras gene is mutated in 20% of human cancers. Therefore, deciphering the molecular function of Ets-1 and Ets-2 within Ras-dependent signal transduction will provide new insight and guide development of new tools to confront the cancer problem.

描述（由申请人提供）：拟议研究的长期目标是了解如何在真核调节转录因子家族中确定特异性。 ETS基因家族在整个后生动物中都有27个人类旁系同源物。 ETS蛋白具有高度保守的DNA结合特性，但显示出独特的不同生物学特性。因此，特异性必须演变为指示这些蛋白质在独特的生物学环境中起作用。该提案的重点是信号通路如何影响ETS蛋白的功能以提供不同的活性。目的我研究了ETS-1 DNA结合的自身抑制作用，包括通过钙依赖性磷酸化的增强。生化和生物物理方法将测试蛋白质动力学和构象变化在ETS-1 DNA结合调节中的作用。 ETS-1调节的磷酸化依赖性变稳定模型将在体外和细胞中进行测试。 AIM II研究了ETS-1和高度相关的ETS-2作为RAS/MAPINGINASE信号传导的效应子。我们将专注于介导MAPK ERK2对ETS-1和ETS-2的对接的大分子界面以及共激活因子CBP/P300的磷酸化依赖性募集。此外，将研究两个最近发现的ETS-1修改，乙酰化和汇总。 AIM III将确定ETS-1和ETS-2的真实转录靶标，以研究基因组基因座在基因组基因座的ETES-1和ETS-2活性的信号传导如何影响。我们将测试翻译后修饰和因子组装在基因激活和抑制中的作用。 RAS/MAPK信号传导和转录因子的ETS家族调节控制细胞周期，凋亡和正常分化所需的基因。人Ras和ETS基因的突变导致癌症的细胞功能障碍。实际上，RAS基因在20％的人类癌症中被突变。因此，在RAS依赖性信号转导中，将ETS-1和ETS-2的分子功能解密，将提供新的见识，并指导新工具的开发，以面对癌症问题。