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

Nieminen A.I.; Eskelinen V.M.; Haikala H.M.Tervonen T.A.Yan Y.Partanen J.I.Klefstr?m J.

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第20期|e1839-e1848|共2页
作者
Nieminen A.I.; Eskelinen V.M.; Haikala H.M.Tervonen T.A.Yan Y.Partanen J.I.Klefstr?m J.;
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作者单位

Translational Cancer Biology Research Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland;

Institute of Biotechnology, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Cancer metabolism; Cell death; Oncogene;

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

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