AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.
Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
Jones
Russell G
RG
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Plas
David R
DR
Kubek
Sara
S
Buzzai
Monica
M
Mu
James
J
Xu
Yang
Y
Birnbaum
Morris J
MJ
Thompson
Craig B
CB
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose