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The coordinate regulation of the p53 and mTOR pathways in cells

PNAS, 7 June 2005
Vol. 102, Issue 23, p. 8204-8209
DOI: 10.1073/pnas.0502857102

The coordinate regulation of the p53 and mTOR pathways in cells

  1. Zhaohui Feng * , ,
  2. Haiyan Zhang * , , ,
  3. Arnold J. Levine * , § , , and
  4. Shengkan Jin * , ,
  1. *Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 08903; 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
  1. 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.

  • AMP-activated kinase
  • autophagy
  • tuberous sclerosis 1/tuberous sclerosis 2

Footnotes

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

  • Z.F. and H.Z. contributed equally to this work.

  • 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.

  • 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.

  • Freely available online through the PNAS open access option.

Citation:

Z. Feng, H. Zhang, A. J. Levine, and S. Jin, The coordinate regulation of the p53 and mTOR pathways in cells. PNAS 102, 8204-8209 (2005).

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