Factors involved in GLUT-1 glucose transporter gene transcription in cardiac muscle.
Glucose constitutes a major fuel for the heart, and high glucose uptake during fetal development is coincident with the highest level of expression of the glucose transporter GLUT-1 during life. We have previously reported that GLUT-1 is repressed perinatally in rat heart, and GLUT-4, which shows a low level of expression in the fetal stage, becomes the main glucose transporter in the adult. Here, we show that the perinatal expression of GLUT-1 and GLUT-4 glucose transporters in heart is controlled directly at the level of gene transcription. Transient transfection assays show that the -99/-33 fragment of the GLUT-1 gene is sufficient to drive transcriptional activity in rat neonatal cardiomyocytes. Electrophoretic mobility shift assays demonstrate that the transcription factor Sp1, a trans-activator of GLUT-1 promoter, binds to the -102/-82 region of GLUT-1 promoter during the fetal state but not during adulthood. Mutation of the Sp1 site in this region demonstrates that Sp1 is essential for maintaining a high transcriptional activity in cardiac myocytes. Sp1 is markedly down-regulated both in heart and in skeletal muscle during neonatal life, suggesting an active role for Sp1 in the regulation of GLUT-1 transcription. In all, these results indicate that the expression of GLUT-1 and GLUT-4 in heart during perinatal development is largely controlled at a transcriptional level by mechanisms that might be related to hyperplasia and that are independent from the signals that trigger cell hypertrophy in the developing heart. Furthermore, our results provide the first functional insight into the mechanisms regulating muscle GLUT-1 gene expression in a live animal.
Santalucía
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Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Diagonal 645, Universitat de Barcelona, Barcelona 08028, Spain.
Boheler
K R
KR
Brand
N J
NJ
Sahye
U
U
Fandos
C
C
Viñals
F
F
Ferré
J
J
Testar
X
X
Palacín
M
M
Zorzano
A
A
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis; D018507:Gene Expression Regulation, Developmental; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006321:Heart / Q000196:embryology / Q000254:growth & development; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000235:genetics; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D016329:Sp1 Transcription Factor