title: Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway.
abstract: Solid tumors often have an inadequate blood supply, which results in large regions that are subjected to hypoxic or anoxic stress. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates much of the transcriptional response of cells to hypoxia. Activating transcription factor 3 (ATF3) is another transcription factor that responds to a variety of stresses and is often upregulated in cancer. We investigated the regulation of ATF3 by oxygen deprivation. ATF3 induction occurred most robustly under anoxia, is common, and it is not dependent on presence of HIF-1 or p53, but is sensitive to the inhibition of c-Jun NH2-terminal kinase activation and the antioxidant N-acetylcystein. ATF3 could also be induced by desferrioxamine but not by the mitochondrial poison cyanide or the nonspecific 2-oxoglutarate dioxygenase inhibitor dimethyloxalylglycine. We also show that anoxic ATF3 mRNA is more stable than normoxic mRNA providing a mechanism for this induction. Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. kameri@stanford.edu
authors.forename: K
authors.initials: K
authors.lastname: Ameri
authors.forename: E M
authors.initials: EM
authors.lastname: Hammond
authors.forename: C
authors.initials: C
authors.lastname: Culmsee
authors.forename: M
authors.initials: M
authors.lastname: Raida
authors.forename: D M
authors.initials: DM
authors.lastname: Katschinski
authors.forename: R H
authors.initials: RH
authors.lastname: Wenger
authors.forename: E
authors.initials: E
authors.lastname: Wagner
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
authors.forename: T
authors.initials: T
authors.lastname: Hai
authors.forename: N
authors.initials: N
authors.lastname: Denko
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured / Q000378:metabolism / Q000473:pathology; D003486:Cyanides / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000111:Acetylcysteine; D051700:Activating Transcription Factor 3; D000600:Amino Acids, Dicarboxylic; D051792:Basic Helix-Loop-Helix Proteins; D003486:Cyanides; D003676:Deferoxamine; D016166:Free Radical Scavengers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006899:Mixed Function Oxygenases; D010100:Oxygen; D016755:Proto-Oncogene Proteins c-jun; D017262:Siderophores; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human; C040947:oxalylglycine