title: Role of diacylglycerol induced by hypoxia in the regulation of HIF-1alpha activity.
abstract: Hypoxia-inducible factor 1 (HIF-1) is a critical transcription factor for the adaptation to lowered oxygen environments. We have previously reported that hypoxia induced phosphatidic acid (PA) accumulation through diacylglycerol kinase (DGK) activity and provided evidence that this PA production regulated HIF-1 expression. Here we report that hypoxia also produces a marked intracellular accumulation of diacylglycerol (DAG) in different cell types. The previously proposed inhibitor of phosphatidylcholine phospholipase C (PC-PLC)/sphingomyelin synthase (SMS) activities, D609, specifically abrogates both hypoxia-dependent DAG accumulation and hypoxia-induced HIF-1 expression. We show that DAG-dependent protein kinase C (PKC) isoforms do not play an essential role in the regulation of HIF-1 expression. D609 inhibits PA accumulation triggered by hypoxia, suggesting that DAG could act as substrate for its conversion into PA by DGK upon these conditions. Therefore, this work provides novel evidence for the existence of DAG/PA-dependent intracellular mechanisms involved in the regulation of HIF-1 expression.
authors.affiliation: Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid (UAM), c/Diego de León 62, 28006 Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Temes
authors.forename: Silvia
authors.initials: S
authors.lastname: Martín-Puig
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Gemma
authors.initials: G
authors.lastname: Olmos
authors.forename: Isabel
authors.initials: I
authors.lastname: Mérida
authors.forename: Manuel O
authors.initials: MO
authors.lastname: Landázuri
mesh_terms: D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004075:Diglycerides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D009636:Norbornanes; D010712:Phosphatidic Acids / Q000096:biosynthesis; D043265:Phosphatidylinositol Diacylglycerol-Lyase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D021122:Protein Subunits; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D001952:Bridged-Ring Compounds; D004075:Diglycerides; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D009636:Norbornanes; D010712:Phosphatidic Acids; D010726:Phosphodiesterase Inhibitors; D021122:Protein Subunits; D013859:Thiocarbamates; D013871:Thiones; D014157:Transcription Factors; C046498:tricyclodecane-9-yl-xanthogenate; D008156:Luciferases; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D002118:Calcium; C064758:Ro 31-8220