Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1.
We used mouse hepatoma (Hepa1c1c7) cells to study the role of the serine/threonine kinase Akt in the induction of GLUT1 gene expression. In order to selectively turn on the Akt kinase cascade, we expressed a hydroxytamoxifen-regulatable form of Akt (myristoylated Akt1 estrogen receptor chimera (MER-Akt1)) in the Hepa1c1c7 cells; we verified that hydroxytamoxifen stimulates MER-Akt1 activity to a similar extent as the activation of endogenous Akt by insulin. Our studies reveal that stimulation of MER-Akt1 by hydroxytamoxifen induces GLUT1 mRNA and protein accumulation to levels comparable to that induced by insulin; therefore, activation of the Akt cascade suffices to induce GLUT1 gene expression in this cell system. Furthermore, expression of a kinase-inactive Akt mutant partially inhibits the response of the GLUT1 gene to insulin. Additional studies reveal that the induction of GLUT1 mRNA by Akt and by insulin reflects increased mRNA synthesis and not decreased mRNA degradation. Our findings imply that the GLUT1 gene responds to insulin at the transcriptional level and that Akt mediates a step in the activation of GLUT1 gene expression in this system.
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.
A
A
Barthel
S T
ST
Okino
J
J
Liao
K
K
Nakatani
J
J
Li
J P
JP
Whitlock
R A
RA
Roth
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D051272:Glucose Transporter Type 1; D007328:Insulin / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D051272:Glucose Transporter Type 1; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt