Abstract
The hexokinases, by converting glucose to glucose 6-phosphate, help maintain the glucose concentration gradient that results in the movement of glucose into cells through the facilitative glucose transporters. Hexokinase II (HKII) is the major hexokinase isoform in skeletal muscle, heart, and adipose tissue. Insulin induces HKII gene transcription in L6 myotubes, and this, in turn, increases HKII mRNA and the rates of HKII protein synthesis and glucose phosphorylation in these cells. Inhibitors of distinct insulin signaling pathways were used to dissect the molecular mechanism by which HKII gene expression is induced by insulin in L6 myotubes. Treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), or with rapamycin, an inhibitor of the pathway from the insulin receptor to p70/p85 ribosomal S6 protein kinase (p70(s6k)), prevented the induction of HKII mRNA by insulin. In contrast, treatment with PD98059, an inhibitor of mitogen-activated protein kinase activation, had no effect on insulin-induced HKII mRNA. In addition, rapamycin blocked the insulin-induced expression of an HKII promoter-chloramphenicol acetyltransferase fusion gene transiently transfected into L6 myotubes, whereas PD98059 had no such effect. These results suggest that a phosphatidylinositol 3-kinase/p70(s6k)-dependent pathway is required for regulation of HKII gene transcription by insulin and that the Ras-mitogen-activated protein kinase-dependent pathway is probably not involved.
Highlights
The binding of insulin to a specific cell-surface receptor results in the activation of an intrinsic receptor tyrosine kinase prevented the induction of Hexokinase II (HKII) mRNA by insulin
These results suggest that a phosphatidylinositol 3-kinase/p70s6k-dependent pathway is required for regulation of HKII gene transcription by insulin and that the Ras-mitogen-activated protein kinase-dependent pathway is probably not involved
We have previously shown that insulin increases the rate of HKII gene transcription in L6 myotubes [4], and insulin does not affect HKII mRNA stability
Summary
The binding of insulin to a specific cell-surface receptor results in the activation of an intrinsic receptor tyrosine kinase prevented the induction of HKII mRNA by insulin. Rapamycin blocked the insulin-induced expression of an HKII promoter-chloramphenicol acetyltransferase fusion gene transiently transfected into L6 myotubes, whereas PD98059 had no such effect These results suggest that a phosphatidylinositol 3-kinase/p70s6k-dependent pathway is required for regulation of HKII gene transcription by insulin and that the Ras-mitogen-activated protein kinase-dependent pathway is probably not involved. The four mammalian hexokinases (ATP:D-hexose-6-phosphotransferase, EC 2.7.1.1; designated HKI through IV) are a family of closely related enzymes that convert glucose to glucose 6-phosphate (for review, see Ref. 1) This enzymatic step nin blocks the activation of p70/p85 ribosomal S6 protein kinase (p70s6k) by insulin or insulin-like growth factor-1 (IGF1), so it is presumed that p70s6k requires PI 3-kinase for its activation by these agents [13, 22, 23].
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