title: A nonapoptotic role for BAX and BAK in eicosanoid metabolism.
abstract: BCL-2 proteins are key regulators of programmed cell death. The interplay between pro and antiapoptotic BCL-2 members has important roles in many cancers. In addition to their apoptotic function, recent evidence supports key nonapoptotic roles for several BCL-2 proteins. We used an unbiased lipidomics strategy to reveal that the proapoptotic proteins BAX, and to a lesser extent BAK, regulate the cellular inflammatory response by mediating COX-2 expression and prostaglandin biosynthesis. COX-2 upregulation in response to the bacterial endotoxin lipopolysaccharide is blunted in the absence of BAX, and Bax(-/-) mouse embryonic fibroblasts display altered kinetics of NFκB and MAPK signaling following endotoxin treatment. Our approach uncovers a novel, nonapoptotic function for BAX in regulation of the cellular inflammatory response and suggests that inflammation and apoptosis are more tightly connected than previously anticipated.
authors: †Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, United States.
authors: Tejia
authors: T
authors: Zhang
authors: ‡Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, United States.|§Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States.
authors: Loren D
authors: LD
authors: Walensky
authors: †Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, United States.
authors: Alan
authors: A
authors: Saghatelian
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics*
chemical_list: C494772:BAK1 protein, human; C494827:Bax protein, mouse; D015777:Eicosanoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases