P27KIP1 EXPRESSION, A PROGNOSTIC INDICATOR==BUT WHY?

P27KIP1 表达，一个预后指标==但是为什么呢？

• 批准号: 6233528
• 负责人: ANDREW KOFF
• 金额: $ 35.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-20 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6233528
• 关键词: apoptosis; breast neoplasms; cell cycle proteins; cyclin dependent kinase; cyclins; dopamine receptor; enzyme inhibitors; gene expression; laboratory mouse; neoplasm /cancer genetics; neoplastic growth; oncoproteins; p53 gene /protein; pituitary neoplasms; prognosis; prostate neoplasms; protein kinase; retinoblastoma protein

The goal of this proposal is to understand why the loss of p27kip1 expression is a strong prognostic indicator for tumor development in many types of human cancer. This proposal examines two alternative hypotheses: First, that the loss of p27 may accelerate cell proliferation making the cell refractory to the negative growth influences of the surrounding cells; or second, that the loss of p27 may eliminate oncogene-induced apoptosis by "desensitizing" the cell to negative growth regulatory signals. In Aim 1, these two models will be examined in the development of pituitary tumors in Rb+/- and Rb+/-;p27-/- mice. Aim 2 will investigate the relationship between p27-deficiency and p53-mdm2-Arf induced apoptosis in the pituitary tumor mouse model, and in human breast and prostate tumor samples. Aim 3 will characterize the growth, apoptosis and transformation properties of mouse embryonic fibroblasts derived from Rb-/-;p27-/- embryos. A 4th Aim is proposed in the supplementary information that is based on the recent finding of Adenocarcinomas in p107+/-;p130-/-;p27-/- mice. This section will extend the analysis of Rb+/-;p27-/- mice to other pocket protein/p27 combinations to determine how loss of p27 modulates their tumor suppressor properties.

该提案的目标是了解为什么 p27kip1 丢失 表达是许多类型肿瘤发展的强有力的预后指标 人类癌症。该提案检验了两个替代假设：首先， p27 的缺失可能会加速细胞增殖，使细胞难以抵抗 周围细胞的负面生长影响；或者第二， p27 的缺失可能通过“脱敏”来消除癌基因诱导的细胞凋亡 细胞产生负生长调节信号。在目标 1 中，这两个模型将是 研究人员对 Rb+/- 和 Rb+/-;p27-/- 小鼠垂体肿瘤的发展进行了检查。 目标 2 将研究 p27 缺陷与 p53-mdm2-Arf 之间的关系 在垂体瘤小鼠模型以及人类乳腺癌和乳腺癌中诱导细胞凋亡 前列腺肿瘤样本。目标 3 将描述生长、凋亡和 小鼠胚胎成纤维细胞的转化特性 Rb-/-；p27-/- 胚胎。补充信息中提出了第四个目标 这是基于最近发现的腺癌 p107+/-;p130-/-;p27-/- 小鼠。本节将扩展分析 Rb+/-;p27-/- 小鼠与其他口袋蛋白/p27 组合以确定如何 p27 的缺失会调节其肿瘤抑制特性。