P27KIP1 EXPRESSION, A PROGNOSTIC INDICATOR==BUT WHY?

这项提议的目标是理解为什么p27kip1的丢失 在许多类型的肿瘤中，表达是一个强有力的预后指标 人类癌症的风险。这项提议考察了两种替代假设：第一， P27的丢失可能会加速细胞的增殖，使细胞对 第二，周围细胞的负面生长影响；第二， P27的缺失可能通过使肿瘤细胞脱敏而消除癌基因诱导的细胞凋亡。 细胞对负生长的调控信号。在目标1中，这两个模型将是 在Rb/-和Rb/-；p27-/-小鼠的脑垂体瘤的发展过程中进行检查。 目的2探讨p27缺陷与P53-MDM2-Arf的关系 在垂体瘤小鼠模型中诱导细胞凋亡，在人乳房和 前列腺癌样本。目标3将描述细胞的生长、凋亡和 小鼠胚胎成纤维细胞转化特性的研究 Rb-/-；p27-/-胚胎。补充信息中提出了第四个目标 这是基于最近在中国发现的腺癌 P107/-；p130-/-；p27-/-小鼠。这一部分将扩展对 Rb/-；p27-/-小鼠与其他口袋蛋白/p27结合，以确定如何 P27的缺失调节了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.