title: Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis.
abstract: 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.
authors.affiliation: Translational Cancer Biology Research Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Anni I
authors.initials: AI
authors.lastname: Nieminen
authors.forename: Vilja M
authors.initials: VM
authors.lastname: Eskelinen
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Haikala
authors.forename: Topi A
authors.initials: TA
authors.lastname: Tervonen
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Johanna I
authors.initials: JI
authors.lastname: Partanen
authors.forename: Juha
authors.initials: J
authors.lastname: Klefström
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C494773:Bak1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D012694:Serine; D055372:AMP-Activated Protein Kinases
keywords: cancer metabolism; cell death; oncogene