Analysis of the Signaling Pathway Involved in the Regulation of Hexokinase II Gene Transcription by Insulin

Osawa, Haruhiko; Sutherland, Calum; Robey, R. Brooks; Printz, Richard L.; Granner, Daryl K.

doi:10.1074/jbc.271.28.16690

Cited by 126Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

Analysis of the Signaling Pathway Involved in the Regulation of Hexokinase II Gene Transcription by Insulin

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Osawa, Haruhiko, Sutherland, Calum, Robey, R. Brooks, Printz, Richard L., Granner, Daryl K.·1996·Journal of Biological Chemistry

DOI 10.1074/jbc.271.28.16690

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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.

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PI3K inhibitors impair glucose transport and block activation of glycogen synthase and HK-II expression.
“Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase- (HK-) II expression [138–146]”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [146]

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Authors: Osawa, H., Sutherland, C., Robey, R. B., Printz, R. L., & Granner, D. K.
Affiliations: Vanderbilt University (US)
Corresponding author: Granner, Daryl K.
ORCID: Osawa, Haruhiko
Sutherland, Calum
Robey, R. Brooks
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1996-07
Volume: 271
Issue: 28
Pages: 16690-16694
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.271.28.16690
OpenAlex: W2026369967
Cited by: 126
References: 41
Citations by year: 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 1
FWCI: 3.03
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8862 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
Funders: U.S. Department of Health and Human Services
Vanderbilt University (DK20593)
National Institutes of Health (5r01dk046867-09)
Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center (DK-20593)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-46867, DK42502, DK35107)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: hexokinase 2, insulin signaling, gene transcription, phosphatidylinositol 3-kinase, p70 S6 kinase, rapamycin, wortmannin, mitogen-activated protein kinase, L6 myotubes, glucose phosphorylation, Ras signaling, skeletal muscle
MeSH terms: Wortmannin, Adipose Tissue, Androstadienes, Animals, Cell Line, Enzyme Inhibitors, Flavonoids, Hexokinase, Insulin, Insulin Antagonists, Monosaccharide Transport Proteins, Muscle Proteins, Myocardium, Polyenes, RNA, Messenger, Transcription, Genetic, Signal Transduction, Muscle, Skeletal, Sirolimus, Glucose Transporter Type 4, Rats

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Analysis of the Signaling Pathway Involved in the Regulation of Hexokinase II Gene Transcription by Insulin

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