TOR is a highly conserved protein serine/threonine kinase and the specific target of the anticancer drug rapamycin and rapamycin analogs (rapalogs). It is a central controller of cell growth and metabolism. PI3K-TOR pathway is mutated in over 50% of human tumors, resulting in TOR hyper-activation and uncontrolled cancer growth. Because of the cancer addiction the pathway, TOR is recognized as a major target for anti-cancer drug therapy. TOR regulation of translational initiation is a well known mechanism of growth control. Because translation is predominantly a cytoplasmic event, TOR has been historically viewed as a classical cytoplasmic kinase. However, we have observed that TOR is localized in the nucleus and binds to the promoters of ribosomal genes to stimulate their expression. We further showed that blocking this process is important for rapamycin to inhibit cell growth. Emerging evidence indicates that control of gene expression, particularly genes involved in ribosome biogenesis and other genes involved in protein synthesis and metabolic biosynthesis, is an important mechanism for TOR to promote protein synthesis and metabolism. Dysregulation of these processes has been linked to tumorigenesis and other TOR-related diseases. In contrast to translational control, the understanding of transcriptional regulation and other nuclear functions by TOR signaling is very limited. In this application, we will test the hypothesis that TOR has a broad role in rapamycin- sensitive transcription and other genomic functions inside the nucleus. We will further investigate the molecular mechanisms by which rapamycin represses ribosomal and other protein biosynthetic genes through Maf1 and Rpd3. Accomplishment of this proposal should provide invaluable new insights into TOR-regulated nuclear process that is poorly understood but highly relevant to the biology and therapy of cancer and metabolic diseases.

Public Health Relevance

TOR is a protein that governs cell growth and metabolism in response to growth signals from outside. Frequent mutations render TOR as a major driver of uncontrolled cancer growth, underlying its significance in cancer biology and treatment. Rapamycin and rapamycin analogs (rapalogs) are highly specific inhibitors of TOR, which are currently used in the clinic to treat advanced renal cancer. TOR is also known to play an important role in the pathogenesis of several other human diseases, including aging, cardiac hypertrophy, diabetes, muscular dystrophy, Parkinson's disease and polycystic kidney disease (PKD). Rapamycin has been shown to be useful to treat many of the aforementioned diseases in experimental models. Therefore, research to further understand how TOR functions in the cell and how rapamycin acts to disrupt pathological processes is highly significant. In this proposal, we will investigate a novel area of TOR signaling that regulates expression of genes critical for cell growth and metabolism. Accomplishment of our goals will provide important molecular insights into these cellular processes that underlie human diseases and rapamycin's therapeutic activity. Accomplishment of our goals in this application should help improve TOR-directed anticancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123391-07
Application #
8444399
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Spalholz, Barbara A
Project Start
2006-07-01
Project End
2013-06-30
Budget Start
2013-03-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$74,745
Indirect Cost
$26,831
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
Thomas, Janice D; Zhang, Yan-Jie; Wei, Yue-Hua et al. (2014) Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell 26:754-69
Tsang, Chi Kwan; Liu, Yuan; Thomas, Janice et al. (2014) Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance. Nat Commun 5:3446
Zhang, Yanjie; Zheng, X F Steven (2012) mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors. Cell Cycle 11:594-603
Zhang, Yan-Jie; Duan, Yanwen; Zheng, X F Steven (2011) Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 16:325-31
Tsang, Chi Kwan; Liu, Hui; Zheng, X F Steven (2010) mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. Cell Cycle 9:953-7
Wei, Yuehua; Tsang, Chi Kwan; Zheng, X F Steven (2009) Mechanisms of regulation of RNA polymerase III-dependent transcription by TORC1. EMBO J 28:2220-30
Tsang, Chi Kwan; Zheng, X F Steven (2009) Opposing role of condensin and radiation-sensitive gene RAD52 in ribosomal DNA stability regulation. J Biol Chem 284:21908-19
Wei, Yuehua; Zheng, X F Steven (2009) Sch9 partially mediates TORC1 signaling to control ribosomal RNA synthesis. Cell Cycle 8:4085-90