CENTRAL ROLE FOR PHOSPHATIDYLINOSITIDE 3-KINASE IN THE REPRESSION OF GLUCOSE-6-PHOSPHATASE GENE-TRANSCRIPTION BY INSULIN

Transcription of the gene encoding the catalytic subunit of glucose-6- phosphatase (G6Pase) is stimulated by glucocorticoids and strongly rep ressed by insulin. We have explored the signaling pathways by which in sulin mediates the repression of G6Pase transcription in H4IIE cells. Wortmannin, a phosphatidylinositide 3-kinase (PtdIns 3-kinase) inhibit or blocked the repression of G6Pase mRNA expression by insulin. Howeve r, both rapamycin, which inhibits p70S6 kinase activation, and PD98059 , an inhibitor of mitogen-activated protein kinase activation, were wi thout effect. Insulin inhibited dexamethasone-induced luciferase expre ssion from a transiently transfected plasmid that places the luciferas e gene under the control of the G6Pase promoter. This effect of insuli n was mimicked by the overexpression of a constitutively active PtdIns 3-kinase but not by a constitutively active protein kinase B. Taken t ogether, these data demonstrate that PtdIns 3-kinase activation is bot h necessary and at least partly sufficient for the repression of G6Pas e expression by insulin, but neither mitogen-activated protein kinase nor p70S6 kinase are involved. In addition, activation of protein kina se B alone is not sufficient for repression of the G6Pase gene. These results imply the existence of a novel signaling pathway downstream of PtdIns 3 kinase that is involved in the regulation of G6Pase expressi on by insulin.