Cyclin E in growth control and tumorogenesis

描述(申请人提供)：细胞周期蛋白E是一种重要的细胞周期调节蛋白。同时，在人类患者和小鼠模型中，细胞周期蛋白E表达的失控都与癌症的发生有关。目前的提案是一个正在进行的项目，旨在了解Cyclin E的正常调控方式，并分别阐明Cyclin E表达解除调控和促进癌症发生的机制。该提案分为三个具体目标，第一个目标是研究细胞周期蛋白E在培养细胞和小鼠体内的降解机制。我们将探讨细胞周期蛋白E上特定的磷酸化位点的作用，以及由F-box蛋白hCDC4定义的一种新的SCF蛋白泛素连接酶的作用。第二个特定目标是针对Cyclin E解除调控导致基因组不稳定的机制，这可能是Cyclin E介导的致癌过程中的一个促成因素。我们将详细探讨两个假说：Cyclin E的解除调控通过干扰复制前复合体的组装而损害DNA的复制，以及有丝分裂中Cyclin 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)来阻止中期-后期转换。最终的具体目标是寻求更好地了解细胞周期蛋白E去调控和致癌之间的联系。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基因杂合性缺失(LOH)而促进肿瘤的发生。人们希望这些调查将提供见解，最终将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.