Structural mechanisms of FoxM1 regulation

FoxM1调节的结构机制

基本信息

批准号：
10092190
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
项目类别：
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/10092190
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

项目摘要

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.

项目摘要该研究项目的目的是表征调节FOXM1的分子机制细胞增殖。 FOXM1转录因子增加了基因表达以驱动细胞周期和分配。在许多人类癌细胞中，FOXM1表达和活性很高，因此是必需的，因此 FOXM1是一个有吸引力的治疗靶点。我们提出并将测试FOXM1的新结构模型调节，其中活性通过固有无序的构象切换来调节反式激活结构域（TAD）。我们将确定无效FOXM1的结构，其中TAD为由负调节域（NRD）结合并隔离。我们还将检验假设的假设依赖细胞周期蛋白和类似polo的激酶磷酸化FOXM1，从NRD释放TAD，并增强结合转录共激活蛋白CBP的螺旋结构。这些研究会通过多站点磷酸化为细胞周期控制提供基本的新见解，并告知开发抑制FOXM1及其在细胞分裂中作用的治疗剂的未来策略。