Regulation of Cyclin-dependent Kinase Inhibitor p27

细胞周期蛋白依赖性激酶抑制剂 p27 的调节

• 批准号: 6919314
• 负责人: MONG-HONG LEE
• 金额: $ 26.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919314
• 关键词: athymic mouse; biological models; breast neoplasms; chemotherapy; clinical research; cyclin dependent kinase; gene delivery system; gene therapy; human tissue; immunocytochemistry; inhibitor /antagonist; neoplasm /cancer genetics; neoplastic process; paclitaxel; protein kinase; protooncogene; transfection; tumor suppressor proteins; western blottings

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the roles of cyclin-dependent kinase inhibitor p27 in cancer and its regulation by oncogenic signals. p27 is a new class of tumor suppressor and is haplo-insufficient in tumor suppression. Decreased expression of the p27 protein was shown to correlate with cancer development and poor survival rates, and is an important marker of cancer progression. Overexpression of HER2, a proto-oncogene, was reported to correlate with poor survival rates in cancer patients. Many cancers affected by HER2 overexpression, including breast, colon, gastric, lung, and ovarian cancers, are the cancers with decreased p27 expression. Little is known about the possible link between HER2 overexpression and low p27 expression in cancers. Based on the low level expression pattern of p27 in HER2-overexpressing breast cancer samples and cancer cell lines, we hypothesize that a link between these two important prognostic markers exists. Our studies showed that HER2 oncogenic signals cause enhanced ubiquitin-mediated p27 degradation and can lead to nuclear exporting of Jab1/p27 complex. Also, we showed that p27 expression in HER2-overexpressing mouse-derived tumors reduces the tumor volumes in a mouse model. To further understand the molecular mechanism of the regulation between these two important prognostic markers, we will determine the mechanism of HER2-mediated p27 degradation by characterizing the molecular regulation of Jabi, a p27 exporter, and SCF-SKP2 ubiquitin ligase complex in response to HER2 activity. Finally, we will explore the tumor expression activity of p27 to find an optimal therapeutic strategy for HER2-overexpressing breast cancers. We expect that these studies will greatly enrich our understanding of HER2-mediated p27 degradation in cancer and will help develop p27 as a novel therapeutic agent for HER2-associated cancers.

描述（由申请人提供）：该提案的目的是阐明细胞周期蛋白依赖性激酶抑制剂p27在癌症中的作用及其通过致癌信号调节。 p27是一类新的肿瘤抑制剂，在肿瘤抑制中是一单元的不足。显示p27蛋白的表达降低与癌症发展和存活率差有关，并且是癌症进展的重要标志。据报道，HER2的过表达与癌症患者的存活率差有关。许多受HER2过表达影响的癌症，包括乳腺癌，结肠，胃，肺和卵巢癌，是P27表达降低的癌症。关于HER2过表达与癌症低p27表达之间可能的联系知之甚少。基于在过表达HER2的乳腺癌样品和癌细胞系中p27的低水平表达模式，我们假设存在这两个重要的预后标记之间存在联系。我们的研究表明，HER2致癌信号会导致泛素介导的P27降解增强，并可能导致JAB1/P27复合物的核输出。另外，我们表明，在过表达HER2的小鼠衍生肿瘤中的p27表达会减少小鼠模型中的肿瘤体积。为了进一步了解这两个重要的预后标记之间调节的分子机制，我们将通过表征JABI的分子调节P27出口剂和SCF-SKP2泛素蛋白 - 泛素 - 泛素 - 泛素 - 泛素 - 泛素 - 泛素蛋白络合物复合物，通过表征HER2介导的p27降解的机制。活动。最后，我们将探索p27的肿瘤表达活性，以找到用于过表达HER2乳腺癌的最佳治疗策略。我们预计这些研究将极大地丰富我们对HER2介导的P27癌症降解的理解，并将有助于开发P27作为HER2相关癌症的新型治疗剂。