P27KIP1 EXPRESSION, A PROGNOSTIC INDICATOR==BUT WHY?

这项研究的目的是了解为什么p27 kip 1基因的缺失 在许多类型中，表达是肿瘤发展的强预后指标 人类癌症这一建议审查了两个备选假设：第一， p27的缺失可加速细胞增殖， 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”癌基因而消除癌基因诱导的凋亡。 细胞负向生长调节信号。在目标1中，这两个模型将 在Rb+/-和Rb+/-;p27-/-小鼠垂体瘤的发展中进行了检查。 目的2探讨p27缺陷与p53-mdm 2-Arf的关系 在垂体瘤小鼠模型和人乳腺癌中诱导细胞凋亡， 前列腺肿瘤样本。目的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。补充资料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。本节将扩展对 Rb+/-;p27-/-小鼠与其他口袋蛋白/p27组合，以确定如何 p27的缺失调节它们的肿瘤抑制特性。

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.