EXPRESSION OF CYCLIN E IN GYNECOLOGIC MALIGNANCIES

循环素 E 在妇科恶性肿瘤中的表达

• 批准号: 6193664
• 负责人: DONNA R SESSION
• 金额: $ 20.11万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-18 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193664
• 关键词: carcinoma; cell line; cervix neoplasms; cyclin dependent kinase; cyclins; enzyme inhibitors; estrogens; female; gene expression; hormone regulation /control mechanism; human tissue; ovary neoplasms; progesterone; uterus neoplasms; women's health

DESCRIPTION: (Adopted from the application)The cyclins and their catalytic partners, cyclin-dependent kineses (Cdks) are key regulators of the cell cycle. Overexpression of cyclin genes has been described in several forms of human cancers. Preliminary evidence suggests that cyclin E is expressed in a subset of gynecological cancers, namely clear cell carcinoma of the ovary, endometrium and cervix. The first specific aim will focus on confirming the specificity of cyclin E for clear cell tumors of Mullerian origin. Expression of cyclin E will be assessed in different histological subtypes of epithelial ovarian, endometrial, cervical and renal cancers. Cyclin E specificity for gynecologic clear cell carcinomas may provide a useful diagnostic marker to help distinguish a pelvic tumor of Mullerian versus non-Mullerian origin. This may have important implications in cases when the primary lesion is unknown since the therapy for ovarian and renal malignancies differs. Histological subtype specific aberrations in cyclin/Cdk expression may be important implications in the potential success of future therapies targeting Cdks. The first generation of these inhibitors are being evaluated in clinical trials. The second specific aim will evaluate steroid hormonal regulation of cyclin E using an in vitro model. The effects of estrogen and progesterone on cyclin E activity will be assessed using an ovarian cancer cell line. Increasing evidence suggests a role for hormones in the etiology of gynecologic malignancies. Moreover, cyclins have been shown to be regulated by estrogen and progesterone in breast cancer cell lines. The role of hormones in the development of reproductive tract cancer has important implications in the treatment of menopause and may also contribute to the direction of future therapeutic and preventative agents. Specific aim three will evaluate the expression and activity of cyclin dependent kinase inhibitors in order to elucidate the mechanism of aberrant cyclin E activity. The activity of a cyclin/Cdk is dependent upon the association with cyclin dependent kinase inhibitors (CdkIs). This specific aim will attempt to correlate cyclin E activity with the CdkIs, p2 1 and p27 in gynecologic malignancies. In addition, the role of estrogen and progesterone on CdkI association with cyclin E will be determined. Interestingly, it appears that the increase cyclin E activity in breast cancer cell lines in response to steroid hormones is mediated through alterations in the Cdk-inhibitory proteins. Understanding the mechanisms of cyclin E aberrations may lead to powerful and convenient models for studying potential tumor promoters, markers and antiproliferative agents.

描述：（从应用程序中采用）细胞周期蛋白及其催化 合作伙伴，依赖细胞周期蛋白依赖性的辐射（CDK）是细胞周期的关键调节剂。 细胞周期蛋白基因的过表达已被描述为几种形式的人类 癌症。初步证据表明，细胞周期蛋白E在子集中表达 妇科癌，即卵巢，子宫内膜的细胞癌 和子宫颈。第一个具体目的将重点是确认 细胞周期蛋白E，用于穆勒来起源的透明细胞肿瘤。细胞周期蛋白E的表达将 在上皮卵巢的不同组织学亚型中进行评估， 子宫内膜，宫颈和肾癌。细胞周期蛋白特异性的妇科特异性 清除细胞癌可能会提供有用的诊断标记来帮助 区分穆勒式与非毛刺起源的骨盆肿瘤。这可能 在主要病变未知的情况下，具有重要的含义 卵巢和肾脏恶性肿瘤的疗法有所不同。组织学亚型 细胞周期蛋白/CDK表达中的特定畸变可能是重要的含义 针对CDK的未来疗法的潜在成功。第一代 这些抑制剂中正在评估临床试验。第二个特定 AIM将使用体外评估细胞周期蛋白E的类固醇激素调节 模型。雌激素和孕酮对细胞周期蛋白E活性的影响将是 使用卵巢癌细胞系进行评估。越来越多的证据表明 用于妇科恶性肿瘤病因的激素。而且，细胞周期蛋白 已显示乳腺癌中的雌激素和孕酮调节 细胞系。激素在生殖道发展中的作用 癌症对更年期的治疗具有重要意义，也可能 促进未来治疗和预防剂的方向。 特定目标三将评估细胞周期蛋白的表达和活性 依赖激酶抑制剂，以阐明异常机制 细胞周期蛋白活性。细胞周期蛋白/CDK的活性取决于 与细胞周期蛋白依赖性激酶抑制剂（CDKI）的关联。这个特定的目标 将尝试将Cyclin E活性与CDKI相关联，P2 1和P27 妇科恶性肿瘤。另外，雌激素和孕酮的作用 将确定与细胞周期蛋白E的CDKI关联。有趣的是，它看起来很像 响应于 类固醇激素是通过CDK抑制性的改变来介导的 蛋白质。了解细胞周期蛋白异常的机制可能导致 强大且方便的模型，用于研究潜在的肿瘤启动子，标记 和抗增生剂。