Article
- The EMBO Journal (2007) 26, 4812 - 4823
- doi:10.1038/sj.emboj.7601900
Published online: 25 October 2007
Subject Categories:
Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53
Chung-Han Lee1,2, Ken Inoki1,2, Magdalena Karbowniczek3, Emmanuel Petroulakis4, Nahum Sonenberg4, Elizabeth Petri Henske3 and Kun-Liang Guan1,2,5,6
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
- Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada
- Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA
- Present address: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA
Correspondence to:
Kun-Liang Guan, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA. Tel.: +1 734 763 3030; Fax: +1 734 647 9702; E-mail: kunliang@umich.edu or kuguan@ucsd.edu
Received 12 July 2007; Accepted 27 September 2007
Abstract
Miscoordination of growth and proliferation with the cellular stress response can lead to tumorigenesis. Mammalian target of rapamycin (mTOR), a central cell growth controller, is highly activated in some malignant neoplasms, and its clinical implications are under extensive investigation. We show that constitutive mTOR activity amplifies p53 activation, in vitro and in vivo, by stimulating p53 translation. Thus, loss of TSC1 or TSC2, the negative regulators of mTOR, results in dramatic accumulation of p53 and apoptosis in response to stress conditions. In other words, the inactivation of mTOR prevents cell death by nutrient stress and genomic damage via p53. Consistently, we also show that p53 is elevated in TSC tumors, which rarely become malignant. The coordinated relationship between mTOR and p53 during cellular stress provides a possible explanation for the benign nature of hamartoma syndromes, including TSC. Clinically, this also suggests that the efficacy of mTOR inhibitors in anti-neoplastic therapy may also depend on p53 status, and mTOR inhibitors may antagonize the effects of genotoxic chemotherapeutics.
Keywords:
- apoptosis,
- mTOR,
- p53,
- rapamycin
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