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.

Public Health Relevance

How cells alter their gene expression in response to their nutrient environment is essential for normal cell function and is fundamentally corrupted in many diseases, including cancer, diabetes, and metabolic disease. This project will define how a specific nutrient sensing pathway interacts with the machinery controlling gene expression to regulate cell growth control.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Maas, Stefan
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University of Tennessee Health Science Center
Schools of Medicine
United States
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Laribee, R Nicholas (2018) Transcriptional and Epigenetic Regulation by the Mechanistic Target of Rapamycin Complex 1 Pathway. J Mol Biol 430:4874-4890
Chen, Hongfeng; Sirupangi, Tirupataiah; Wu, Zhao-Hui et al. (2018) The conserved RNA recognition motif and C3H1 domain of the Not4 ubiquitin ligase regulate in vivo ligase function. Sci Rep 8:8163
Workman, Jason J; Chen, Hongfeng; Laribee, R Nicholas (2016) Saccharomyces cerevisiae TORC1 Controls Histone Acetylation by Signaling Through the Sit4/PP6 Phosphatase to Regulate Sirtuin Deacetylase Nuclear Accumulation. Genetics 203:1733-46
Chen, Hongfeng; Workman, Jason J; Strahl, Brian D et al. (2016) Histone H3 and TORC1 prevent organelle dysfunction and cell death by promoting nuclear retention of HMGB proteins. Epigenetics Chromatin 9:34
Laribee, R Nicholas; Hosni-Ahmed, Amira; Workman, Jason J et al. (2015) Ccr4-not regulates RNA polymerase I transcription and couples nutrient signaling to the control of ribosomal RNA biogenesis. PLoS Genet 11:e1005113
Fasken, Milo B; Laribee, R Nicholas; Corbett, Anita H (2015) Nab3 facilitates the function of the TRAMP complex in RNA processing via recruitment of Rrp6 independent of Nrd1. PLoS Genet 11:e1005044
Workman, Jason J; Chen, Hongfeng; Laribee, R Nicholas (2014) Environmental signaling through the mechanistic target of rapamycin complex 1: mTORC1 goes nuclear. Cell Cycle 13:714-25