Growth Control and Anti-Cancer Mechanisms

描述(申请人提供)：生长是通过积累新合成的蛋白质来增加细胞质量和大小的过程。它被认为是肿瘤发生中的一个重要过程，这是支持癌细胞快速增殖(细胞数量增加)所必需的。蛋白质合成的速度由翻译起始和核糖体的丰度决定。产生核糖体或核糖体生物发生涉及数百个基因和所有三种RNA聚合酶，占核转录的90%。核糖体的生物合成是高耗能的，并且受到生长因子和营养物质的严格控制。人们早就知道，在癌细胞中，翻译机制的组成部分被解除管制或错误表达。一些肿瘤抑制基因和原癌基因，如视网膜母细胞瘤(Rb)蛋白、P53、PTEN和Myc，已经被证明是针对核糖体生物发生的。雷帕霉素是一种很有前途的抗癌新药，目前正在进行大规模临床试验。它的耐受性很好，对许多人类癌症显示出极好的疗效。我们最近获得的证据表明，抑制核糖体生物发生是雷帕霉素抑制细胞生长的关键，并发现了雷帕霉素抑制核糖体生物发生的几种新机制。在这个提案中，我们将研究核糖体生物发生、核仁大小控制和雷帕霉素抑制的调控机制。这些目标的实现将促进对雷帕霉素的生长控制、肿瘤发生和作用机制的理解。此外，这类研究可能导致更有效的抗癌治疗策略，并有助于在这一重要但研究较少的癌症治疗领域确定新的癌症药物靶点。

DESCRIPTION (provided by applicant): Growth is the process to increase cell mass and size by accumulation of newly synthesized proteins. It is increasingly appreciated as an important process in tumorigenesis, which is required to support the rapid cancer cell proliferation (an increase in cell number). The rate of protein synthesis is determined by both translational initiation and the abundance of ribosomes. Producing ribosomes or ribosome biogenesis involves several hundred genes and all three RNA polymerases and accounts for 90% nuclear transcription. Ribosome biogenesis is highly energy-consuming and is tightly controlled by growth factors and nutrients. It has been long known that, in cancer cells, components of the translational machinery are deregulated or misexpressed. Several tumor suppressors and proto-oncogenes, such as the retinoblastoma (Rb) protein, p53, PTEN and Myc, have been shown to target ribosome biogenesis. Rapamycin is a promising new anticancer drug currently under large clinical trials. It is well tolerated and has shown excellent efficacy for many human cancers. We have recently obtained evidence that inhibition of ribosome biogenesis is crucial for rapamycin to inhibit cell growth, and discovered several new mechanisms for rapamycin to inhibit ribosome biogenesis. In this proposal, we will investigate the regulatory mechanisms of ribosome biogenesis, nucleolar size control and rapamycin inhibition. Accomplishment of these goals should advance the understanding of growth control, tumorigenesis and the mechanism of action by rapamycin. Additionally, such studies may lead to more effective anticancer therapeutic strategies and help identify new cancer drug targets in this important yet poorly studied area in cancer therapeutics.