CYCLIN E AND GROWTH CONTROL AND TUMOROGENESIS

细胞周期蛋白E作为细胞周期蛋白依赖性激酶CDK2的正向调节因子， 是细胞周期进程的关键调节因子。它也可以成为，当 放松管制，这是肿瘤发生的一个因素。然而，无论是分子还是分子 细胞周期蛋白E刺激细胞周期进程的机制 其参与肿瘤发生的机制已被阐明。这 一项旨在研究细胞周期蛋白E的功能和调控的提案 在正常和肿瘤来源的人乳腺上皮中的这两种情况 细胞，其原理是所获得的信息可能具有 乳房疾病的预防、诊断和治疗的最终意义 癌症。研究计划包括四个具体目标。第一 通过消除细胞周期蛋白E的重要性和功能 利用新型反义寡核苷酸技术表达细胞周期蛋白E。这个 第二个特定目标，也使用反义寡核苷酸技术， 研究乳腺上皮细胞调节的机制 细胞周期蛋白E相关的CDK2激酶活性维持在适当水平 增殖反应。第三个具体目标直接涉及 细胞周期蛋白E基因失控导致恶性转化的机制 转型。组织培养模型被用来研究 细胞周期蛋白E过表达与遗传不稳定性的关系 而转基因小鼠模型被用来直接探测 细胞周期蛋白E失控导致乳腺癌发生的机制。 最后，第四个具体目标寻求调查是否 Cyclin E蛋白降解或成熟的解除调控在Cyclin中的作用 E在与肿瘤发生相关的条件下的积累。因为 试剂和技术已经可以用来进行大多数 在这些研究中，预计可以在以下方面取得快速进展 所有的研究途径都建议。

Cyclin E, as a positive regulator of the cyclin-dependent kinase, Cdk2, is a key regulator of cell cycle progression. It can also become, when deregulated, a factor in oncogenesis. However, neither the molecular mechanisms whereby cyclin E stimulates cell cycle progression nor those whereby it participates in oncogenesis have been elucidated. This proposal seeks to investigate the function and regulation of cyclin E in both contexts in normal and tumor-derived human breast epithelial cells, the rationale being that information gained is likely to have eventual implications for prevention, diagnosis and therapy of breast cancer. The research plan consists of four specific aims. The first addresses the issue of cyclin E essentiality and function by eliminating cyclin E expression via novel antisense oligonucleotide technology. The second specific aim, also using antisense oligonucleotide technology, investigates the mechanisms whereby breast epithelial cells regulate cyclin E-associated Cdk2 kinase activity to maintain an appropiate proliferative response. The third specific aim directly addresses the mechanism whereby cyclin E deregulation leads to malignant transformation. Tissue culture models are used to investigate the relationship between cyclin E overexpression and genetic instability, whereas a transgenic mouse model is used to directly probe the mechanisms whereby cyclin E deregulation causes mammary carcinogenesis. Finally, the fourth specific aim seeks to investigate whether deregulation of cyclin E proteolysis or maturation play a role in cyclin E accumulation under conditions associated with oncogenesis. Because reagents and technology are already available for carrying out most of these studies, it is anticipated that rapid progress can be achieved on all research avenues proposed.