Regulation of GLUT1 gene transcription by the serine threonine kinase Akt1

We used mouse hepatoma (Hepa1c1c7) cells to study the role of the serine/th reonine kinase Akt in the induction of GLUT1 gene expression. In order to s electively 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 hydroxytamox ifen induces GLUT1 mRNA and protein accumulation to levels comparable to th at 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 GLUT 1 gene to insulin. Additional studies reveal that the induction of GLUT1 mR NA by Akt and by insulin reflects increased mRNA synthesis and not decrease d mRNA degradation. Our findings imply that the GLUT1 gene responds to insu lin at the transcriptional level and that Akt mediates a step in the activa tion of GLUT1 gene expression in this system.