Details

Autor(en) / Beteiligte

• Nieminen, Anni I
• Eskelinen, Vilja M
• Haikala, Heidi M
• Tervonen, Topi A
• Yan, Yan
• Partanen, Johanna I
• Klefström, Juha

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2013-05, Vol.110 (20), p.E1839-E1848

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-x L interaction. Further liberation of Bak specifically from the p53-activated Bak–Bcl-x L 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.