The role of Cyclin E in growth control and tumorogenesis

描述（由申请人提供）：Cyclin E是一种关键的细胞周期调节蛋白。与此同时，在人类患者和小鼠模型中，细胞周期蛋白E表达的失调与癌变有关。目前的提案构成了一个正在进行的项目，旨在了解细胞周期蛋白E是如何正常调节的，并阐明细胞周期蛋白E表达失控和促进癌变的机制。该提案分为三个具体目标，其中第一个是解决细胞周期蛋白E在培养细胞和小鼠中的降解机制。我们将探索细胞周期蛋白E上特定磷酸化位点的作用，以及F-box蛋白hCdc4定义的一种新的SCF蛋白泛素连接酶的作用。第二个具体目标是针对细胞周期蛋白E解除管制导致基因组不稳定的机制，这可能是细胞周期蛋白E介导的致癌的一个促成因素。本文将详细探讨两种假设：细胞周期蛋白E的失调通过干扰复制前复合体组装而损害DNA复制；有丝分裂中细胞周期蛋白E水平的升高通过抑制必要的有丝分裂蛋白泛素连接酶（APC）而阻断了中期到后期的转变。最后一个具体目标是寻求更好地理解细胞周期蛋白E解除管制与癌变之间的联系。小鼠模型将被用来确定细胞周期蛋白E是否通过加速肿瘤抑制位点杂合性（LOH）的丧失来促进癌变。希望这些研究将提供见解，最终导致改善预后和治疗。

DESCRIPTION (provided by applicant): Cyclin E is a critical cell cycle regulatory protein. At the same time, deregulation of cyclin E expression has been linked to carcinogenesis both in human patients and in mouse models. The current proposal constitutes an ongoing project aimed at gaining understanding into how cyclin E is normally regulated and to elucidate the mechanisms whereby cyclin E expression becomes deregulated and promotes carcinogenesis, respectively. The proposal is divided into three specific aims, the first of which addresses the mechanism of cyclin E degradation in cultured cells and in mice. The role of specific phosphorylation sites on cyclin E will be explored as well as the contribution of a new SCF protein ubiquitin ligase defined by the F-box protein hCdc4. The second specific aim is targeted at the mechanism whereby deregulation of cyclin E confers genomic instability, likely to be a contributing factor in cyclin E-mediated carcinogenesis. Two hypotheses will be explored in detail: that deregulation of cyclin E impairs DNA replication by interfering with pre-replication complex assembly and that elevated cyclin E levels in mitosis block the metaphase-anaphase transition by inhibiting the essential mitotic protein ubiquitin ligase known as APC. The final specific aim seeks to gain a better understanding of the link between cyclin E deregulation and carcinogenesis. Mouse models will be employed to determine if cyclin E promotes carcinogenesis by accelerating loss of heterozygosity (LOH) at tumor suppressor loci. It is hoped that these investigations will provide insights that will ultimately lead to improved prognosis and therapy.