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Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells.

Publication ,  Journal Article
Edinger, AL; Linardic, CM; Chiang, GG; Thompson, CB; Abraham, RT
Published in: Cancer Res
December 1, 2003

Rapamycin and its analogues have shown promising anticancer activities in preclinical and clinical studies. However, the mechanism whereby rapamycin inhibits signaling through the mammalian target of rapamycin (mTOR) remains poorly understood. Here, we show that the FKBP12/rapamycin complex is an essentially irreversible inhibitor of mTOR kinase activity in vitro. However, we observe no suppression of mTOR catalytic activity after immunoprecipitation from rapamycin-treated cells. These results suggest either that rapamycin acts as a reversible kinase inhibitor in intact cells or that the cellular effects of rapamycin are not mediated through global suppression in mTOR kinase activity. To better understand the cellular pharmacology of rapamycin, we compared the individual and combined effects of rapamycin and kinase-inactive mTOR expression on a panel of mTOR-dependent cellular responses. These studies identified glycolytic activity, amino acid transporter trafficking, and Akt kinase activity as novel, mTOR-modulated functions in mammalian cells. Whereas kinase-inactive mTOR did not enhance the decreases in cell size and glycolysis induced by rapamycin, expression of this mTOR mutant significantly enhanced the inhibitory effects of rapamycin on cell proliferation, 4EBP1 phosphorylation, and Akt activity. Unexpectedly, amino acid transporter trafficking was perturbed by kinase-inactive mTOR but not by rapamycin, indicating that this process is rapamycin insensitive. These results indicate that rapamycin exerts variable inhibitory actions on mTOR signaling functions and suggest that direct inhibitors of the mTOR kinase domain will display substantially broader anticancer activities than rapamycin.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

December 1, 2003

Volume

63

Issue

23

Start / End Page

8451 / 8460

Location

United States

Related Subject Headings

  • Transfection
  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Signal Transduction
  • Protein Kinases
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Humans
  • Cell Size
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Edinger, A. L., Linardic, C. M., Chiang, G. G., Thompson, C. B., & Abraham, R. T. (2003). Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res, 63(23), 8451–8460.
Edinger, Aimee L., Corinne M. Linardic, Gary G. Chiang, Craig B. Thompson, and Robert T. Abraham. “Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells.Cancer Res 63, no. 23 (December 1, 2003): 8451–60.
Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res. 2003 Dec 1;63(23):8451–60.
Edinger, Aimee L., et al. “Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells.Cancer Res, vol. 63, no. 23, Dec. 2003, pp. 8451–60.
Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res. 2003 Dec 1;63(23):8451–8460.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

December 1, 2003

Volume

63

Issue

23

Start / End Page

8451 / 8460

Location

United States

Related Subject Headings

  • Transfection
  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Signal Transduction
  • Protein Kinases
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Humans
  • Cell Size