title: Functional importance of Dicer protein in the adaptive cellular response to hypoxia.
abstract: The processes by which cells sense and respond to ambient oxygen concentration are fundamental to cell survival and function, and they commonly target gene regulatory events. To date, however, little is known about the link between the microRNA pathway and hypoxia signaling. Here, we show in vitro and in vivo that chronic hypoxia impairs Dicer (DICER1) expression and activity, resulting in global consequences on microRNA biogenesis. We show that von Hippel-Lindau-dependent down-regulation of Dicer is key to the expression and function of hypoxia-inducible factor α (HIF-α) subunits. Specifically, we show that EPAS1/HIF-2α is regulated by the Dicer-dependent microRNA miR-185, which is down-regulated by hypoxia. Full expression of hypoxia-responsive/HIF target genes in chronic hypoxia (e.g. VEGFA, FLT1/VEGFR1, KDR/VEGFR2, BNIP3L, and SLC2A1/GLUT1), the function of which is to regulate various adaptive responses to compromised oxygen availability, is also dependent on hypoxia-mediated down-regulation of Dicer function and changes in post-transcriptional gene regulation. Therefore, functional deficiency of Dicer in chronic hypoxia is relevant to both HIF-α isoforms and hypoxia-responsive/HIF target genes, especially in the vascular endothelium. These findings have relevance to emerging therapies given that we show that the efficacy of RNA interference under chronic hypoxia, but not normal oxygen availability, is Dicer-dependent. Collectively, these findings show that the down-regulation of Dicer under chronic hypoxia is an adaptive mechanism that serves to maintain the cellular hypoxic response through HIF-α- and microRNA-dependent mechanisms, thereby providing an essential mechanistic insight into the oxygen-dependent microRNA regulatory pathway.
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5B 1W8, Canada.
authors: J J David
authors: JJ
authors: Ho
authors: Julie L
authors: JL
authors: Metcalf
authors: Matthew S
authors: MS
authors: Yan
authors: Paul J
authors: PJ
authors: Turgeon
authors: Jenny Jing
authors: JJ
authors: Wang
authors: Maria
authors: M
authors: Chalsev
authors: Tania N
authors: TN
authors: Petruzziello-Pellegrini
authors: Albert K Y
authors: AK
authors: Tsui
authors: Jeff Z
authors: JZ
authors: He
authors: Helena
authors: H
authors: Dhamko
authors: H S Jeffrey
authors: HS
authors: Man
authors: G Brett
authors: GB
authors: Robb
authors: Bin T
authors: BT
authors: Teh
authors: Michael
authors: M
authors: Ohh
authors: Philip A
authors: PA
authors: Marsden
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D043244:Ribonuclease III / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053487:DEAD-box RNA Helicases; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D035683:MicroRNAs; D010100:Oxygen; D011518:Proto-Oncogene Proteins; D043244:Ribonuclease III; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C116838:BNIP3L protein, human; C552431:MIRN185 microRNA, human; C495677:SLC2A1 protein, human; C467484:VEGFA protein, human; C501162:FLT1 protein, human; C408087:DICER1 protein, human; C497446:VHL protein, human