Structural mechanisms of FoxM1 regulation

FoxM1调节的结构机制

• 批准号: 10334450
• 负责人: Seth Michael Rubin
• 金额: $ 27.26万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-21 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334450
• 关键词: Acetyltransferase; Adopted; Affinity; Binding; Binding Proteins; Biochemical; Biological Assay; Biophysics; CREBBP gene; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell division; Cells; Complex; Cyclin-Dependent Kinases; Cyclins; Data; Defect; Disease; Docking; Event; FOXM1 gene; Future; Gene Expression; Genetic Transcription; Goals; Health; Human; Kinetics; Left; Licensing; Link; Malignant Neoplasms; Mitotic; Modeling; Molecular; Molecular Conformation; Neoplasm Metastasis; Oncogenic; Oranges; PLK1 gene; Phosphorylation; Phosphotransferases; Process; Prognosis; Proteins; Regulation; Research Project Grants; Role; Site; Structural Models; Structure; Testing; Therapeutic; Transactivation; Transcription Coactivator; Transcriptional Activation; Work; base; cancer cell; cell growth; insight; novel; polo-like kinase kinase 1; promoter; recruit; success; therapeutic target; transcription factor; tumorigenesis

Project Summary The goal of this research project is to characterize the molecular mechanisms regulating FoxM1 in cell proliferation. The FoxM1 transcription factor increases gene expression to drive the cell cycle and division. FoxM1 expression and activity are high and necessary in many human cancer cells, and thus FoxM1 is an attractive therapeutic target. We propose and will test a novel structural model for FoxM1 regulation, in which activity is modulated by conformational switching of an intrinsically disordered transactivation domain (TAD). We will determine the structure of inactive FoxM1, in which the TAD is bound and sequestered by a negative regulatory domain (NRD). We will also test hypotheses for how Cyclin-dependent and Polo-like kinases phosphorylate FoxM1, releasing the TAD from the NRD and enhancing a helical structure that binds the transcription coactivator protein CBP. These studies will provide fundamental new insights into cell cycle control through multisite phosphorylation and inform future strategies for developing therapeutics that inhibit FoxM1 and its role in cell division.

项目摘要 本研究项目的目标是表征在人乳腺癌中调节FoxM 1的分子机制。 细胞增殖FoxM 1转录因子增加基因表达以驱动细胞周期， 师. FoxM 1的表达和活性在许多人类癌细胞中是高的和必需的，因此， FoxM 1是一个有吸引力的治疗靶点。我们提出并将测试一种新的FoxM 1结构模型 调节，其中活性通过内在无序的构象转换来调节， 反式激活结构域（transactivation domain，RT-PCR）。我们将确定不活跃的FoxM 1的结构，其中， 由负调控域（NRD）结合和隔离。我们还将测试假设如何 细胞周期蛋白依赖性激酶和Polo样激酶磷酸化FoxM 1，从NRD释放FoxM 1， 增强结合转录共激活蛋白CBP的螺旋结构。这些研究将 通过多位点磷酸化为细胞周期控制提供了基本的新见解， 开发抑制FoxM 1及其在细胞分裂中作用的治疗方法的未来策略。