title: The transcriptional co-repressor myeloid translocation gene 16 inhibits glycolysis and stimulates mitochondrial respiration.
abstract: The myeloid translocation gene 16 product MTG16 is found in multiple transcription factor-containing complexes as a regulator of gene expression implicated in development and tumorigenesis. A stable Tet-On system for doxycycline-dependent expression of MTG16 was established in B-lymphoblastoid Raji cells to unravel its molecular functions in transformed cells. A noticeable finding was that expression of certain genes involved in tumor cell metabolism including 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4 (PFKFB3 and PFKFB4), and pyruvate dehydrogenase kinase isoenzyme 1 (PDK1) was rapidly diminished when MTG16 was expressed. Furthermore, hypoxia-stimulated production of PFKFB3, PFKFB4 and PDK1 was inhibited by MTG16 expression. The genes in question encode key regulators of glycolysis and its coupling to mitochondrial metabolism and are commonly found to be overexpressed in transformed cells. The MTG16 Nervy Homology Region 2 (NHR2) oligomerization domain and the NHR3 protein-protein interaction domain were required intact for inhibition of PFKFB3, PFKFB4 and PDK1 expression to occur. Expression of MTG16 reduced glycolytic metabolism while mitochondrial respiration and formation of reactive oxygen species increased. The metabolic changes were paralleled by increased phosphorylation of mitogen-activated protein kinases, reduced levels of amino acids and inhibition of proliferation with a decreased fraction of cells in S-phase. Overall, our findings show that MTG16 can serve as a brake on glycolysis, a stimulator of mitochondrial respiration and an inhibitor of cell proliferation. Hence, elevation of MTG16 might have anti-tumor effect.
authors.affiliation: Department of Hematology, Lund University, Lund, Sweden.
authors.forename: Parveen
authors.initials: P
authors.lastname: Kumar
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Sharoyko
authors.forename: Peter
authors.initials: P
authors.lastname: Spégel
authors.forename: Urban
authors.initials: U
authors.lastname: Gullberg
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Inge
authors.initials: I
authors.lastname: Olsson
authors.forename: Ram
authors.initials: R
authors.lastname: Ajore
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006019:Glycolysis; D006801:Humans; D020935:MAP Kinase Signaling System; D008928:Mitochondria / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D010101:Oxygen Consumption; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C115744:CBFA2T3 protein, human; C000631429:PDK1 protein, human; C506672:PFKFB4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D017346:Protein Serine-Threonine Kinases; D048055:Mitogen-Activated Protein Kinase 8