title: The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression.
abstract: Tumorigenesis is associated with enhanced cellular glucose uptake and increased metabolism. Because the p53 tumor suppressor is mutated in a large number of cancers, we evaluated whether p53 regulates expression of the GLUT1 and GLUT4 glucose transporter genes. Transient cotransfection of osteosarcoma-derived SaOS-2 cells, rhabdomyosarcoma-derived RD cells, and C2C12 myotubes with GLUT1-P-Luc or GLUT4-P-Luc promoter-reporter constructs and wild-type p53 expression vectors dose dependently decreased both GLUT1 and GLUT4 promoter activity to approximately 50% of their basal levels. PG(13)-Luc activity, which was used as a positive control for functional p53 expression, was increased up to approximately 250-fold by coexpression of wild-type p53. The inhibitory effect of wild-type p53 was greatly reduced or abolished when cells were transfected with p53 with mutations in amino acids 143, 248, or 273. A region spanning -66/+163 bp of the GLUT4 promoter was both necessary and sufficient to mediate the inhibitory effects of p53. Furthermore, in vitro translated p53 protein was found to bind directly to two sequences in that region. p53-DNA binding was completely abolished by excess unlabeled probe but not by nonspecific DNA and was super-shifted by the addition of an anti-p53 antibody. Taken together, our data strongly suggest that wild-type p53 represses GLUT1 and GLUT4 gene transcription in a tissue-specific manner. Mutations within the DNA-binding domain of p53, which are usually associated with malignancy, were found to impair the repressive effect of p53 on transcriptional activity of the GLUT1 and GLUT4 gene promoters, thereby resulting in increased glucose metabolism and cell energy supply. This, in turn, would be predicted to facilitate tumor growth.
authors.affiliation: Institute of Endocrinology, Diabetes, and Metabolism, Rambam Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Schwartzenberg-Bar-Yoseph
authors.forename: Michal
authors.initials: M
authors.lastname: Armoni
authors.forename: Eddy
authors.initials: E
authors.lastname: Karnieli
mesh_terms: D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000166:cytology; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D016159:Tumor Suppressor Protein p53