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. ? ? ?
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