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-tubulin
1 Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, and 2 Departments of Pharmacology, 3 Pathology, and 4 Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425
Increased flux through the
hexosamine biosynthesis pathway has been implicated in the development
of glucose-induced insulin resistance and may promote the modification
of certain proteins with O-linked
N-acetylglucosamine (O-GlcNAc). L6 myotubes (a
model of skeletal muscle) were incubated for 18 h in 5 or 25 mM
glucose with or without 10 nM insulin. As assessed by immunoblotting
with an O-GlcNAc-specific antibody, high glucose and/or
insulin enhanced O-GlcNAcylation of numerous proteins,
including the transcription factor Sp1, a known substrate for this
modification. To identify novel proteins that may be
O-GlcNAc modified in a glucose
concentration/insulin-responsive manner, total cell membranes were
separated by one- or two-dimensional gel electrophoresis. Selected
O-GlcNAcylated proteins were identified by mass spectrometry
(MS) analysis. MS sequencing of tryptic peptides identified member(s)
of the heat shock protein 70 (HSP70) family and rat 
-tubulin.
Immunoprecipitation/immunoblot studies demonstrated several HSP70
isoforms and/or posttranslational modifications, some with selectively
enhanced O-GlcNAcylation following exposure to high glucose
plus insulin. In conclusion, in L6 myotubes, Sp1, membrane-associated
HSP70, and -tubulin are O-GlcNAcylated; the modification
is markedly enhanced by sustained increased glucose flux.
insulin resistance; L6 myotubes; O-linked N-acetylglucosamine; heat shock protein 70
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