title: Myeloid translocation gene-16 co-repressor promotes degradation of hypoxia-inducible factor 1.
abstract: The myeloid translocation gene 16 (MTG16) co-repressor down regulates expression of multiple glycolytic genes, which are targets of the hypoxia-inducible factor 1 (HIF1) heterodimer transcription factor that is composed of oxygen-regulated labile HIF1α and stable HIF1β subunits. For this reason, we investigated whether MTG16 might regulate HIF1 negatively contributing to inhibition of glycolysis and stimulation of mitochondrial respiration. A doxycycline Tet-On system was used to control levels of MTG16 in B-lymphoblastic Raji cells. Results from co-association studies revealed MTG16 to interact with HIF1α. The co-association required intact N-terminal MTG16 residues including Nervy Homology Region 1 (NHR1). Furthermore, electrophoretic mobility shift assays demonstrated an association of MTG16 with hypoxia response elements (HREs) in PFKFB3, PFKFB4 and PDK1 promoters in-vitro. Results from chromatin immunoprecipitation assays revealed co-occupancy of these and other glycolytic gene promoters by HIF1α, HIF1β and MTG16 in agreement with possible involvement of these proteins in regulation of glycolytic target genes. In addition, MTG16 interacted with prolyl hydroxylase D2 and promoted ubiquitination and proteasomal degradation of HIF1α. Our findings broaden the area of MTG co-repressor functions and reveal MTG16 to be part of a protein complex that controls the levels of HIF1α.
authors.affiliation: Department of Hematology, Lund University, Lund, Sweden.
authors.forename: Parveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Hematology, Lund University, Lund, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Gullberg
authors.affiliation: Department of Hematology, Lund University, Lund, Sweden.
authors.forename: Inge
authors.initials: I
authors.lastname: Olsson
authors.affiliation: Department of Hematology, Lund University, Lund, Sweden.
authors.forename: Ram
authors.initials: R
authors.lastname: Ajore
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C497396:ARNT protein, human; C115744:CBFA2T3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631429:PDK1 protein, human; C506672:PFKFB4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex