Mechanisms of transcription coregulator usage by the target of rapamycin pathway

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DESCRIPTION (provided by applicant): Nutrient and energy availability are key determinants for driving cell growth and proliferation. However, the mechanisms by which nutrient and energy levels are transmitted to the gene expression machinery controlling cell growth and proliferation are still poorly understood. The target of rapamycin (TOR) pathway is an evolutionarily conserved signaling pathway found from budding yeast to man. TOR responds to nutrient and energy levels to control gene expression necessary for cell growth and proliferation. This pathway is deregulated in many diseases, including cancer, diabetes, obesity and multiple neurological syndromes. As such, TOR is of fundamental importance to human health. This proposal will use a budding yeast model system to examine how the TOR pathway signals to the evolutionarily conserved transcriptional co-regulatory complex, Ccr4-Not, to regulate gene expression processes essential for cell growth and proliferation. Ccr4-Not is required for mammalian embryogenesis and embryonic stem cell maintenance and Ccr4-Not defects are linked to cancer, obesity and cardiovascular disease. Therefore, defining how TOR utilizes Ccr4-Not to regulate gene expression will have wide-ranging biomedical implications. Aim I of this proposal will be to delineate how TOR regulates Ccr4-Not phosphorylation and complex composition. Aim II will address how TOR regulation of Ccr4-Not controls histone gene expression which is a necessary step in DNA replication and cell proliferation. Aim III will analyze how TOR uses Ccr4-Not to promote the expression and processing of ribosomal RNAs, an essential TOR-regulated process necessary for ribosome production and ultimately, protein synthesis. Upon the completion of this proposal, how the TOR pathway signals through the Ccr4-Not transcriptional co-regulatory complex to control gene expression essential for cell growth and proliferation will have been defined.