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J Biol Chem, Vol. 273, Issue 30, 18751-18759, July 24, 1998
From the Department of Cellular and Molecular Physiology, The
Pennsylvania State University, College of Medicine,
Hershey, Pennsylvania 17033
Transcription of the phosphoenolpyruvate
carboxykinase (PEPCK) gene is induced by glucagon, acting through cAMP
and protein kinase A, and this induction is inhibited by insulin.
Conflicting reports have suggested that insulin inhibits induction by
cAMP by activating the Ras/mitogen-activated protein kinase (MAPK) pathway or by activating the phosphatidylinositol 3-kinase
(PI3-kinase), but not MAPK, pathway. Insulin activated PI3-kinase
phosphorylates lipids that activate protein kinase B (PKB) and
Ca2+/diacylglycerol-insensitive forms of protein
kinase C (PKC). We have assessed the roles of these pathways in insulin
inhibition of cAMP/PKA-induced transcription of PEPCK by using dominant
negative and dominant active forms of regulatory enzymes in the
Ras/MAPK and PKB pathways and chemical inhibitors of PKC isoforms.
Three independently acting inhibitory enzymes of the Ras/MAPK pathway, blocking SOS, Ras, and MAPK, had no effect upon insulin inhibition. However, dominant active Ras prevented induction of PEPCK and also
stimulated transcription mediated by Elk, a MAPK target. Insulin did
not stimulate Elk-mediated transcription, indicating that insulin did
not functionally activate the Ras/MAPK pathway. Inhibitors of
PI3-kinase, LY294002 and wortmannin, abolished insulin inhibition of
PEPCK gene transcription. However, inhibitors of PKC and mutated forms
of PKB, both of which are known downstream targets of PI3-kinase, had
no effect upon insulin inhibition. Dominant negative forms of PKB did
not interfere with insulin inhibition and a dominant active form of PKB
did not prevent induction by PKA. Phorbol ester-mediated inhibition of
PEPCK transcription was blocked by bisindole maleimide and by
staurosporine, but insulin-mediated inhibition was unaffected. Thus,
insulin inhibition of PKA-induced PEPCK expression does not require
MAPK activation but does require activation of PI3-kinase, although
this signal is not transmitted through the PKB or PKC pathways.
Assessment of the Roles of Mitogen-activated Protein Kinase,
Phosphatidylinositol 3-Kinase, Protein Kinase B, and Protein Kinase C
in Insulin Inhibition of cAMP-induced Phosphoenolpyruvate Carboxykinase
Gene Transcription
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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