CHARACTERIZATION OF P53-INDEPENDENT ARF PATHWAY

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 多个遗传步骤导致由p53和视网膜母细胞瘤（Rb）肿瘤抑制因子控制的两种肿瘤抑制因子通路的失调，为人类癌症铺平了道路。p53和Rb蛋白需要上游效应子和激活子之间的通信，以感知细胞何时处于应激状态。由INK 4a/ARF基因座编码的两种蛋白质p16 INK 4a和p19 ARF分别在功能上靶向Rb和p53肿瘤抑制因子。这四种蛋白质是人类癌症中最常受影响的基因之一。我们希望了解这些蛋白质对人类癌症发展的单独贡献，以及它们如何受到上游信号的调控。我们以前表明，ARF是由不适当的促有丝分裂信号，如从Myc和Ras癌蛋白发出的信号，它转移过度增殖细胞进行p53依赖性细胞周期阻滞或凋亡。这是通过ARF的相互作用和p53负调节因子Mdm 2的核仁隔离来实现的。然而，来自我们实验室的越来越多的证据表明，ARF-p53-Mdm 2通路不是严格的线性，为进一步研究核仁内的其他ARF功能打开了大门。 我们的目标是了解ARF肿瘤抑制能力背后的基本机制，并将这些过程与我们对人类癌症进展的不断增长的知识联系起来。此外，ARF似乎拮抗核糖体加工以及成熟核糖体成分的核质穿梭。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple genetic steps that result in the deregulation of two tumor suppressor pathways, governed by the p53 and retinoblastoma (Rb) tumor suppressors, pave the road to cancer in humans. The p53 and Rb proteins require communication between upstream effectors and activators to sense when a cell is under stress. Two proteins encoded by the INK4a/ARF locus, p16INK4a and p19ARF, functionally target the Rb and p53 tumor suppressors, respectively. These four proteins are among the most frequently affected genes in human cancer. We wish to understand the individual contribution of these proteins to the development of human cancers and how they may be regulated by upstream signals. We previously showed that ARF is induced by inappropriate mitogenic signals, such as those emanating from the Myc and Ras oncoproteins, and it diverts hyperproliferating cells to undergo p53-dependent cell cycle arrest or apoptosis. This is accomplished through ARF's interaction and nucleolar sequestration of the p53-negative regulator Mdm2. However, mounting evidence from our lab suggests that the ARF-p53-Mdm2 pathway is not be strictly linear, opening the door for further research into other ARF functions within the nucleolus. Our goal is to understand the basic mechanisms behind ARF's tumor suppressive capabilities and to relate these processes to our growing knowledge of human cancer progression. Additionally, ARF appears to antagonize ribosome processing as well as the nucleocytoplasmic shuttling of maturing ribosomal components.