Cancer and Gene Regulation by the pRB/E2F Pathway

基因调控的改变在肿瘤的发生过程中起着关键作用。我们的研究集中在两种肿瘤上 抑制通路p16lnk4a-CyCD/CDK4-pRb-E2F和p19Art-MDM2-P53，控制着细胞周期蛋白的表达 细胞增殖或肿瘤监视反应所需的基因。我们有 在体内建立了pRb/E2F和An7p53通路之间的直接联系(Aslanian等人，2004年)：特异性 E2F家族成员在正常细胞中对Arf的转录抑制(通过E2F3B)或 /A/FIN肿瘤细胞的转录激活(通过激活E2F)。这项提案中的实验将 使用小鼠模型(以及由此产生的细胞系和肿瘤)和RNAi技术的组合来 了解pRb/E2F通路在调控Arf转录和细胞增殖中的作用。他们 还将确定pRb途径和细胞转化如何影响miRNA调控和 功能。有四个目标：(1)识别E2F3B抑制子复合体；(2)了解 激活E2F诱导Arf和其他肿瘤特异性的E2F反应基因；(3)测试对 激活E2F调节正常和肿瘤细胞；以及(4)筛选协同作用的途径 与pRb共同控制细胞的增殖和存活。

Alterations in gene regulation play a key role in the tumorigenic process. Our research centers on two tumor suppressor pathways, p16lnk4a-cycD/cdk4-pRB-E2F and p19Art-mdm2-p53, that control the expression of genes required for cellular proliferation or the tumor surveillance response respectively. We have established a direct link between the pRB/E2F and An7p53 pathways in vivo (Aslanian et al., 2004): specific E2F family members contribute to either the transcriptional repression of Arf in normal cells (via E2F3B) or the transcriptional activation of /A/fin tumor cells (via the activating E2Fs). Experiments in this proposal will use a combination of mouse models (and the resulting cell lines and tumors) and RNAi technology to understand the role of the pRB/E2F pathway in the control of Arf transcription and cellular proliferation. They will also establish how the pRB pathway and cellular transformation influence miRNA regulation and function. There are four goals: (1) To identify the E2F3B represser complex; (2) To understand how the activating E2Fs induce Arf and other "tumor-specific" E2F-responsive genes; (3) To test the requirement for activating E2Fs in the regulation of normal and tumor cells; and (4) To screen for pathways that synergize with pRB in the control of cell proliferation and survival.