The activation of the p53 pathway by the AMP mimetic AICAR is reduced by inhibitors of the ATM or mTOR kinases

Mech Ageing Dev. Nov-Dec 2011;132(11-12):543-51. doi: 10.1016/j.mad.2011.09.002. Epub 2011 Sep 21.

Abstract

A balanced diet reduces the risk of life-threatening diseases such as diabetes and cancer. A reduced supply of energy at the cellular level leads to an increased concentration of AMP, which, in turn, results in LKB1-mediated activation of the AMPK kinase. The activation of the p53 tumor suppressor protein by metabolic stress has been shown to be mediated by AMPK. Increased intracellular AMP can be mimicked by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). We showed that AICAR activated the p53 pathway in LKB1-deficient cells. This activation was strongly attenuated by two inhibitors of the ATM kinase (caffeine and Ku-55933), which is dysfunctional in ataxia-telanagiectasia patients. In cells with ATM expression silenced by shRNA, AICAR-induced p53 phosphorylation at Ser(15) and Ser(37) was attenuated. Furthermore, p53 activation by AICAR was blocked by rapamycin, a specific inhibitor of the mTOR kinase, which is a crucial regulator of cell growth. Rapamycin did not block p53 activation by resveratrol, which, in contrast to AICAR, induced the DNA damage response, senescence-like growth inhibition, a high level of post-translational modification of p53, and weak upregulation of MDM2 (the negative regulator of p53). Thus, ATM and mTOR participate in the activation of p53 in response to a compound mimicking metabolic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adenosine Monophosphate / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Caffeine / pharmacology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • Gene Knockdown Techniques
  • Humans
  • Models, Biological
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Resveratrol
  • Ribonucleotides / pharmacology*
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Stilbenes / pharmacology
  • Stress, Physiological / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / antagonists & inhibitors*
  • Tumor Suppressor Proteins / genetics

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Protein Kinase Inhibitors
  • Ribonucleotides
  • Stilbenes
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Aminoimidazole Carboxamide
  • Caffeine
  • Adenosine Monophosphate
  • STK11 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide
  • Resveratrol
  • Sirolimus