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PNAS 102 (23): 8204-8209

Copyright © 2005 by the National Academy of Sciences.


The coordinate regulation of the p53 and mTOR pathways in cells

Zhaohui Feng * {dagger}, Haiyan Zhang * {dagger}, {ddagger}, Arnold J. Levine *, §, ¶, and Shengkan Jin *, {ddagger}, ¶

*Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 08903; {ddagger}Department of Pharmacology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, NJ 08854; and §The Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540

Contributed by Arnold J. Levine, April 7, 2005

Abstract: Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.

Key Words: AMP-activated kinase • autophagy • tuberous sclerosis 1/tuberous sclerosis 2

Author contributions: A.J.L. and S.J. designed research; Z.F., H.Z., and S.J. performed research; A.J.L. and S.J. analyzed data; and A.J.L. wrote the paper.

Freely available online through the PNAS open access option.

Abbreviations: mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis; AMPK, AMP-activated kinase; MEF, mouse embryonic fibroblast; PI3K, phosphoinositide 3-kinase; MAP, mitogen-activated protein.

{dagger} Z.F. and H.Z. contributed equally to this work.

To whom correspondence may be addressed. E-mail: alevine{at} or jinsh{at}

© 2005 by The National Academy of Sciences of the USA

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The Mammalian Target of Rapamycin Pathway as a Potential Target for Cancer Chemoprevention.
L. Kopelovich, J. R. Fay, C. C. Sigman, and J. A. Crowell (2007)
Cancer Epidemiol. Biomarkers Prev. 16, 1330-1340
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Tissue-specific Autophagy Alterations and Increased Tumorigenesis in Mice Deficient in Atg4C/Autophagin-3.
G. Marino, N. Salvador-Montoliu, A. Fueyo, E. Knecht, N. Mizushima, and C. Lopez-Otin (2007)
J. Biol. Chem. 282, 18573-18583
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Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMP-activated Protein Kinase Signaling.
P. B. Bokko, L. Francione, E. Bandala-Sanchez, A. U. Ahmed, S. J. Annesley, X. Huang, T. Khurana, A. R. Kimmel, and P. R. Fisher (2007)
Mol. Biol. Cell 18, 1874-1886
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The Regulation of AMPK {beta}1, TSC2, and PTEN Expression by p53: Stress, Cell and Tissue Specificity, and the Role of These Gene Products in Modulating the IGF-1-AKT-mTOR Pathways.
Z. Feng, W. Hu, E. de Stanchina, A. K. Teresky, S. Jin, S. Lowe, and A. J. Levine (2007)
Cancer Res. 67, 3043-3053
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DNA Mismatch Repair Initiates 6-Thioguanine-Induced Autophagy through p53 Activation in Human Tumor Cells.
X. Zeng, T. Yan, J. E. Schupp, Y. Seo, and T. J. Kinsella (2007)
Clin. Cancer Res. 13, 1315-1321
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