Rapamycin is a natural product with anti-microbial, immunosuppressive, and anti-neoplastic activities via its ability to inhibit signal transduction. In both yeast and mammalian cells, rapamycin action is mediated by association with the peptidyl proIy1 isomerase, FKBP12. The FKBP12-rapamycin complex inhibits G1 to 5 phase cell cycle progression, but the mechanisms of cell cycle arrest are unknown. Genetic studies in yeast first implicated the T0R1 and T0R2 gene products as targets of the FKBP12-rapamycin complex. Recently, a mammalian TOR homolog (mTOR) has been identified. The highest degree of identity resides in a carboxy terminal domain with homology to lipid and protein kinases. mTOR autophosphorylates, and this activity is inhibited by FKBP12-rapamycin, but only one other candidate substrate (PHAS-1) has been identified. The TOR proteins have three known functions. One, shared by TOR1 and TOR2, is required for signaling translation initiation and G1 cell cycle progression. This function is conserved in mammalian cells and leads to activation of p70s6k. The second function of TOR2, is the control, via the RH01 and RH02 GTPases, of polarized distribution of the actin cytoskeleton during the cell cycle. Finally, a role for mTOR in preventing apoptosis has been suggested by studies in which rapamycin accelerates apoptosis in cancer cells. However, the precise roles of the TOR proteins in these functions are not yet well understood. The candidate has identified a novel toxic domain of the TOR proteins and proposes to identify effectors of the TOR proteins in yeast and mammalian cells and to study the mechanisms by which the TOR proteins regulate cell cycle progression and apoptosis. Such studies should provide information on the mechanisms of action of the novel TOR inhibitor rapamycin and thereby provide a sound biochemical basis for further analysis of rapamycin and other TOR inhibitors as novel chemotherapy agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-CRB-X (O1))
Program Officer
Springfield, Sanya A
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
Cruz, M Cristina; Goldstein, Alan L; Blankenship, Jill R et al. (2002) Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J 21:546-59
Wang, Ping; Nichols, Connie B; Lengeler, Klaus B et al. (2002) Mating-type-specific and nonspecific PAK kinases play shared and divergent roles in Cryptococcus neoformans. Eukaryot Cell 1:257-72
Cutler, N S; Pan, X; Heitman, J et al. (2001) The TOR signal transduction cascade controls cellular differentiation in response to nutrients. Mol Biol Cell 12:4103-13
Cruz, M C; Goldstein, A L; Blankenship, J et al. (2001) Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. Antimicrob Agents Chemother 45:3162-70
Rohde, J; Heitman, J; Cardenas, M E (2001) The TOR kinases link nutrient sensing to cell growth. J Biol Chem 276:9583-6
Wang, P; Cardenas, M E; Cox, G M et al. (2001) Two cyclophilin A homologs with shared and distinct functions important for growth and virulence of Cryptococcus neoformans. EMBO Rep 2:511-8
Arevalo-Rodriguez, M; Cardenas, M E; Wu, X et al. (2000) Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase. EMBO J 19:3739-49
Cardenas, M E; Cutler, N S; Lorenz, M C et al. (1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev 13:3271-9
Cardenas, M E; Cruz, M C; Del Poeta, M et al. (1999) Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action. Clin Microbiol Rev 12:583-611
Cutler, N S; Heitman, J; Cardenas, M E (1999) TOR kinase homologs function in a signal transduction pathway that is conserved from yeast to mammals. Mol Cell Endocrinol 155:135-42

Showing the most recent 10 out of 13 publications