The Cyclin D1/CDK4 Complex in Hepatocyte Proliferation

描述(申请人提供)：本申请中概述的研究将进一步研究细胞周期蛋白D1/CDK4复合体在肝细胞增殖中的作用。细胞周期蛋白D1是一个重要的增殖控制基因，调节细胞周期的G1期进程，是许多人类癌症的癌基因。到目前为止，我们的研究表明，细胞周期蛋白D1是肝细胞对有丝分裂原、细胞外基质和营养物质反应的关键介质。这项建议的重点将是在我们对肝细胞的研究的基础上，进一步定义细胞周期蛋白D1的新功能。我们发现，除了促进细胞周期进程外，细胞周期蛋白D1还能诱导肝细胞生长(细胞大小增加)和全球蛋白质合成。我们的初步数据表明，细胞周期蛋白D1调节翻译装置的组件，这是一个新的发现。由于促进细胞生长和蛋白质合成是正常和肿瘤增殖的关键部分，对这些途径的进一步研究应该有助于深入了解细胞周期蛋白D1的重要功能。我们还发现，持续的细胞周期蛋白D1表达(在几天内)会导致有丝分裂装置的紊乱和染色体的异常。这表明细胞周期蛋白D1可能促进基因组的不稳定性，这可能是其致癌作用的一个重要组成部分。因此，我们建议研究细胞周期蛋白D1对有丝分裂装置和染色体稳定性的调节。我们希望这些研究能更好地了解细胞周期蛋白D1在肝细胞和其他细胞中的作用。

DESCRIPTION (provided by applicant): The studies outlined in this application will further examine the role of the cyclin D1/cdk4 complex in hepatocyte proliferation. Cyclin D1 is an important proliferation-control gene that regulates progression through G1 phase of the cell cycle and is an oncogene in many human cancers. Our studies to date suggest that cyclin D1 is a pivotal mediator of hepatocyte proliferation in response to mitogens, extracellular matrix, and nutrients. The focus of this proposal will be to further define novel functions of cyclin D1 based on our studies in hepatocytes. We have found that in addition to promoting cell cycle progression, cyclin D1 induces hepatocyte growth (increased cell size) and global protein synthesis. Our preliminary data indicates that cyclin D1 regulates components of the translation apparatus, which is a novel finding. Since enhanced cell growth and protein synthesis are critical parts of normal and neoplastic proliferation, further studies of these pathways should provide insight into important functions of cyclin D1. We have also found that persistent cyclin D1 expression (over a matter of days) induces disturbances of the mitotic apparatus and chromosomal abnormalities. This suggests that cyclin D1 may promote genomic instability, which could be a significant component of its oncogenic effect. We therefore propose to study regulation of the mitotic apparatus and chromosome stability by cyclin D1. Our hope is that these studies will provide a better understanding of the actions of cyclin D1 in hepatocytes and other cells.