Nuclear Accumulation of Cyclin D1 and Oncogenesis

描述（由申请人提供）：我们的长期目标是确定 细胞周期机器如何感知细胞外信号， 转化为受调控的细胞周期进程。具体目标是 建议是定义的作用的位点特异性磷酸化， 调节细胞周期蛋白D1核的进出口，以确定 细胞周期蛋白D1定位与蛋白水解的关系，探讨细胞周期蛋白D1定位与蛋白水解的关系。 细胞周期蛋白D1蛋白是组成性核蛋白的潜在致癌性， 并确定细胞周期蛋白D1依赖性转化的机制。 将使用种间异核体测定来检查 调节细胞周期蛋白D1核输出，体外核输入测定将是 用于直接确定细胞周期蛋白D1核输入的机制。的 对于有效细胞周期蛋白D1蛋白水解核输出的必要性也将被 使用体外和体内技术测定。最后，我们将测试 在S期不能从细胞核中去除细胞周期蛋白D1的假设 是正常细胞增殖的关键， 细胞周期蛋白D1变体，D1-T286 A，其表达受 免疫球蛋白内含子增强子元件，E（mu）。对正常增长的颠覆 信号通路是肿瘤的标志，细胞周期蛋白D1的能力， 作为促有丝分裂传感器，将生长因子信号整合到细胞周期中 进展使其成为癌症的常见靶点。拟议的研究将 确定决定细胞周期蛋白D1亚细胞的调节机制 定位，确定定位在细胞周期蛋白D1积累中的作用，以及 展示细胞如何抑制细胞周期蛋白D1的活性， 肿瘤形成

DESCRIPTION (PROVIDED BY APPLICANT): Our long-term objective is to determine how extra-cellular signals are sensed by the cell cycle machine and then transmitted into regulated cell cycle progression. The specific aims of this proposal are to define the role o the site-specific phosphorylation in the regulation of cyclin D1 nuclear import and export, to determine the relationship between cyclin D1 localization and the proteolysis, to explore the potential oncogenicity of cyclin D1 proteins that are constitutively nuclear, and to determine the mechanism of cyclin D1-dependent transformation. Interspecies heterokaryon assays will be used to examine the parameters that regulate cyclin D1 nuclear export, and in vitro nuclear import assays will be used to directly determine the mechanism(s) of cyclin D1 nuclear import. The necessity of nuclear export for efficient cyclin Dl proteolysis will also be determined using both in vitro and in vivo techniques. Finally, we will test the hypothesis that failure to remove cyclin Dl from the nucleus during S-phase is critical for normal cellular proliferation by creating mice carrying the cyclin D1 variant, D 1-T286A, whose expression is controlled by the immunoglobulin intron enhancer element, E(mu). The subversion of normal growth signaling pathways is a hallmark of neoplasia, and the capacity of cyclin D1 to act as a mitogenic sensor that integrates growth factor signals into cell cycle progression makes it a frequent target in Cancer. The studies proposed will identify the regulatory mechanisms that determine cyclin D1 subcellular localization, determine the role of localization in cyclin D1 accumulation, and demonstrate how cells constrain cyclin D1 activity, thereby preventing neoplasia.