Structural mechanisms of FoxM1 regulation

项目摘要 本研究的目的是研究FOXM1基因调控的分子机制。 细胞增殖。FOXM1转录因子增加基因表达以驱动细胞周期和 组织。FOXM1的高表达和活性在许多人类癌细胞中是必需的，因此 FOXM1是一个有吸引力的治疗靶点。我们提出并将测试FOXM1的一个新的结构模型 调节，其中的活动是通过内在无序的构象转换来调节的。 反式激活结构域(TAD)。我们将确定非活性FOXM1的结构，其中TAD是 被负调控结构域(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和Polo样激酶使FOXM1磷酸化，从NRD和 增强与转录共激活蛋白CBP结合的螺旋结构。这些研究将 通过多位点磷酸化提供对细胞周期控制的基本新见解，并提供 开发抑制FOXM1及其在细胞分裂中的作用的治疗药物的未来战略。

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.