Rapamycin is a bacterially-derived macrolide that is currently undergoing clinical and preclinical evaluations as an immunosuppressant and cancer chemotherapeutic agent. Both the immunosuppressive and anticancer properties of rapamycin are attributed to the inhibition of a signaling pathway required for the passage of proliferating cells from G1 into S phase. A pivotal step toward understanding the anti-proliferative mechanism of rapamycin was the identification of the protein whose function is inhibited when cells are exposed to this drug. The mammalian Target of Rapamycin (mTOR) is a member of a novel family of high molecular weight kinases termed phosphatidylinositol 3-kinase-related kinases (PIKKs). The members of the PIKK family play crucial roles in cell-cycle regulation and chromosome maintenance, and their dysfunction leads to disregulated growth, genomic instability, and cancer. The overall objectives of this proposal are to define the signaling pathway governed by mTOR, and to identify the cell-cycle-related parameters that determine sensitivity or resistance of transformed cells to the anti-proliferative effects of rapamycin. The preliminary studies offer biochemical and genetic evidence that mTOR regulates the translation of mRNAs whose protein products are needed to drive the cell through G1 and into S phase. The current project will extend this research through implementation of three specific aims: (1) to define the role of PHAS-1 in cell growth inhibition by rapamycin, (2) to elucidate upstream regulators of mTOR function in mitogen-stimulated cells, (3) to investigate the interactions of the mTOR-dependent signaling pathway with the cell-cycle control machinery in nontransformed and transformed cells. The completion of these aims may significantly advance ther knowledge of the cellular pharmacology of rapamycin, and will facilitate the development of novel antiproliferative agents targeted against mTOR itself or other components of the mTOR-dependent signaling pathway.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Liu, Enbo; Knutzen, Christine A; Krauss, Sybille et al. (2011) Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci U S A 108:8680-5
Katiyar, Samiksha; Liu, Enbo; Knutzen, Christine A et al. (2009) REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase. EMBO Rep 10:866-72
Chiang, Gary G; Abraham, Robert T (2007) Targeting the mTOR signaling network in cancer. Trends Mol Med 13:433-42
Howes, Amy L; Chiang, Gary G; Lang, Elizabeth S et al. (2007) The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 6:2505-14
Liu, Mei; Howes, Amy; Lesperance, Jacqueline et al. (2005) Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res 65:5325-36
Chiang, Gary G; Abraham, Robert T (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280:25485-90
Chiang, Gary G; Abraham, Robert T (2004) Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase family. Methods Mol Biol 281:125-41
Edinger, Aimee L; Linardic, Corinne M; Chiang, Gary G et al. (2003) Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63:8451-60
Hudson, Christine C; Liu, Mei; Chiang, Gary G et al. (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004-14
McMahon, Lloyd P; Choi, Kin M; Lin, Tai-An et al. (2002) The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol Cell Biol 22:7428-38

Showing the most recent 10 out of 16 publications