Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis

Proc Natl Acad Sci U S A. 2013 May 14;110(20):E1839-48. doi: 10.1073/pnas.1208530110. Epub 2013 Apr 15.


Oncogenic transcription factor Myc deregulates the cell cycle and simultaneously reprograms cellular metabolism to meet the biosynthetic and bioenergetic needs of proliferation. Myc also sensitizes cells to mitochondria-dependent apoptosis. Although metabolic reprogramming has been circumstantially connected to vulnerability to apoptosis, the connecting molecular pathways have remained poorly defined. Here, we show that Myc-induced altered glutamine metabolism involves ATP depletion and activation of the energy sensor AMP-activated protein kinase (AMPK), which induces stabilizing phosphorylation of p53 at Ser15. Under influence of Myc, AMPK-stabilized tumor suppressor protein p53 accumulates in the mitochondria and interacts with the protein complex comprised of B-cell lymphoma 2 (Bcl-2) antagonist/killer (BAK) and Bcl2-like 1 (Bcl-xL). Mitochondrial p53 induces conformational activation of proapoptotic Bak without disrupting the Bak-Bcl-xL interaction. Further liberation of Bak specifically from the p53-activated Bak-Bcl-xL complex leads to spontaneous oligomerization of Bak and apoptosis. Thus, Myc-induced metabolic changes are coupled via AMPK and phospho-p53 to the mitochondrial apoptosis effector Bak, demonstrating a cell-intrinsic mechanism to counteract uncontrolled proliferation.

Keywords: cancer metabolism; cell death; oncogene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Apoptosis*
  • Cell Death
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Damage
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Mitochondria / metabolism*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Conformation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Serine / chemistry
  • Tumor Suppressor Protein p53 / metabolism*
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*
  • bcl-X Protein / metabolism


  • BAK1 protein, human
  • BCL2L1 protein, human
  • Bak1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein
  • Serine
  • AMP-Activated Protein Kinases