Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53.
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.
Lee
Chung-Han
CH
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Inoki
Ken
K
Karbowniczek
Magdalena
M
Petroulakis
Emmanuel
E
Sonenberg
Nahum
N
Henske
Elizabeth Petri
EP
Guan
Kun-Liang
KL
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D005508:Food Deprivation; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006222:Hamartoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D009153:Mutagens; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus