My long-term goal is to understand cell signaling mechanisms to control cell cycle progression in eukaryotic cells. Rapamycin is a potent immunosuppressive and anti-proliferation agent. It is highly effective in treating allograft rejection, autoimmune disorders, fungal infections and cancer. My studies established that Tor1p/Tor2p are the direct targets of rapamycin and led to understanding of the molecular mode of rapamycin action. The target of rapamycin protein or TOR in yeast and its human homolog FKBP12-rapamycin associated protein, FRAP, have recently been identified and shown to be a key regulator in a novel signaling pathway for cell growth, in particular, G1 cell-cycle progression. This pathway is conserved during evolution and delivers signals from growth factors, hormones, cytokines, nutrients and stresses to a cell-cycle checkpoint. The TOR protein family is conserved both structurally and functionally throughout the eukaryotic kingdom. They belong to the phosphatidylinositol kinase (PIK)-related kinase family and have protein a Ser/Thr kinase activity essential for the rapamycin- sensitive growth regulation. However, little is known about TOR protein family as a novel kinase, how its activity is regulated and what the rapamycin-sensitive TOR signaling pathway is composed of. Answering these questions is the next important task in the field, and is the central theme of this proposal. Budding yeast has thus far been a major driving force in the TOR field. This proposed research is aimed at dissecting the mechanisms of TOR signaling with yeast as a model. We will take advantage of all the powerful tools created by the integration of genetics, genomics and molecular biology in S. cerevisiae. Accomplishment of this research should further our general understanding of eukaryotic cell regulation and provide a rational basis for more effective and safer use of rapamycin as a therapeutic agent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA077668-06
Application #
6942853
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Program Officer
Knowlton, John R
Project Start
1999-01-01
Project End
2004-12-31
Budget Start
2004-07-01
Budget End
2004-12-31
Support Year
6
Fiscal Year
2003
Total Cost
$92,229
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Drenan, Ryan M; Liu, Xiangyu; Bertram, Paula G et al. (2004) FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. J Biol Chem 279:772-8
Zheng, Xiaofeng S; Chan, Ting-Fung; Zhou, Heather H (2004) Genetic and genomic approaches to identify and study the targets of bioactive small molecules. Chem Biol 11:609-18
Carvalho, John; Zheng, X F Steven (2003) Domains of Gln3p interacting with karyopherins, Ure2p, and the target of rapamycin protein. J Biol Chem 278:16878-86
Tsang, Chi Kwan; Bertram, Paula G; Ai, Wandong et al. (2003) Chromatin-mediated regulation of nucleolar structure and RNA Pol I localization by TOR. EMBO J 22:6045-56
Choi, Jae H; Bertram, Paula G; Drenan, Ryan et al. (2002) The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. EMBO Rep 3:988-94
Bertram, Paula G; Choi, Jae H; Carvalho, John et al. (2002) Convergence of TOR-nitrogen and Snf1-glucose signaling pathways onto Gln3. Mol Cell Biol 22:1246-52
Chan, T F; Bertram, P G; Ai, W et al. (2001) Regulation of APG14 expression by the GATA-type transcription factor Gln3p. J Biol Chem 276:6463-7