Expression of human ANT2 gene in highly proliferative cells: GRBOX, a new transcriptional element, is involved in the regulation of glycolytic ATP import into mitochondria.
The adenine nucleotide translocator (ANT) is the most abundant mitochondrial inner membrane protein which catalyses the exchange of ADP and ATP between cytosol and mitochondria. The human ANT protein has three isoforms encoded by three differentially regulated nuclear genes. The ANT gene expression was examined in several human cells. The gene encoding the ANT2 isoform was found specifically induced in Simian virus 40 (SV40)-transformed, tumoral and mtDNA lacking rho degrees cell lines. Moreover, the ANT2 gene was preferentially expressed under a glycolytic metabolism. Functional complementation of a Saccharomyces cerevisiae mutant revealed that the human ANT2 protein specifically restores yeast cell growth under anaerobic conditions. Sequence analysis of the ANT2 proximal promoter in comparison to that of the third yeast adenine nucleotide translocator (AAC3) led us to identify a new motif termed GRBOX. Promoter-deletion transfection and mobility gel-shift assays revealed that this motif is recognized by a negative transcriptional regulator. This transcription factor might be involved in a molecular mechanism which selects the import of the glycolytic ATP in the mitochondrial matrix. This ATP import is required in highly proliferative cells, such as tumour cells, which depend strongly on glycolysis for ATP synthesis.
CNRS UMR-5534, Université Claude Bernard Lyon1, 43 Bd du 11 Novembre 1918, Villeurbanne, Cedex, 69622, France. stepien@cissun.univ-lyon1.fr
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Giraud
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Bonod-Bidaud
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Wesolowski-Louvel
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Stepien
D000255:Adenosine Triphosphate / Q000378:metabolism*; D001692:Biological Transport; D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000032:analysis / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000235:genetics
D009687:Nuclear Proteins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D004247:DNA; D000226:Mitochondrial ADP, ATP Translocases