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Research, Medical, and Pathology Services, Veterans Affairs Medical Center of Memphis, and Departments of Medicine, Pharmacology, and Pathology, University of Tennessee, Memphis, Tennessee 38104
Address all correspondence and requests for reprints to: Solomon S. Solomon, M.D., Veterans Affairs Medical Center, Research Service (151), 1030 Jefferson Avenue, Memphis, Tennessee 38104.
Members of the family of Sp transcription factors include Sp1, Sp3, and
Sp4 and are important regulators of eukaryotic gene expression. We
previously reported that Sp1 mediated stimulation of rat calmodulin I
gene expression in response to insulin. To test whether other members
of the Sp family are direct targets of insulin action, we compared the
levels of Sp1 and Sp3 proteins from nuclear extracts obtained from both
insulin-treated and untreated rat hepatoma (H-411E) cells. We
demonstrated by Western blot analysis that levels of Sp1 and Sp3
proteins were increased more than 2-fold in the insulin-treated group.
Additionally, the up-regulation of both Sp1 and Sp3 transcription
factors by insulin was antagonized by tumor necrosis factor-
, a
known inhibitor of insulin action. Immunohistochemical analysis
demonstrated that H-411E cells treated with insulin (10,000 µU/ml)
had a marked increase in demonstrable Sp1 in the nucleus compared with
cells incubated in insulin-free medium. We extended these in
vitro observations to in vivo studies in the
streptozotocin-diabetic rat model. We demonstrated in rat liver tissue
by both Western blot and immunohistochemical staining with anti-Sp1
antibody that 1) livers of fully diabetic streptozotocin rats have low
levels of Sp1 transcription factor; and 2) insulin treatment of the
diabetic rat rapidly reversed this process by markedly stimulating
accumulation of Sp1 in rat liver. Studies of the signal transduction
mechanisms involved in insulin’s effect on Sp1 demonstrate a
facilitating role for phosphoinositol 3-kinase and an inhibitory role
for cyclic nucleotides. In summary, insulin stimulates Sp1 protein, a
transcription factor that is shown to regulate calmodulin gene
expression and most likely other, as yet untested, genes.
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