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Characterization of a Low Affinity Thyroid Hormone Receptor Binding Site within the Rat GLUT4 Gene Promoter

Departments of Biochemistry (C.J.T., G.L.D.) and Medicine (S.J.U.), East Carolina University School of Medicine, Greenville, North Carolina 27858; and the Department of Physiology and Biophysics, University of Iowa (J.E.P.), Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Christopher J. Torrance, Ph.D., Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21231.

Previous studies have demonstrated that thyroid hormone (T₃) stimulates insulin-responsive glucose transporter (GLUT4) transcription and protein expression in rat skeletal muscle. The aim of the present study was to define a putative thyroid hormone response element (TRE) within the rat GLUT4 promoter and thus perhaps determine whether T₃ acts directly to augment skeletal muscle GLUT4 transcription. To this end, electrophoretic mobility shift analyses were performed to analyze thyroid hormone receptor (TR) binding to a previously characterized 281-bp T₃-responsive region of the rat GLUT4 promoter. Indeed, within this region, a TR-binding site of the standard DR+4 TRE variety was located between bases -457/-426 and was shown to posses a specific affinity for in vitro translated TRs. Interestingly, however, the GLUT4 TR-binding site demonstrated a significantly lower affinity compared to a consensus DR+4 TRE, and only bound TRs appreciatively in the form of high affinity heterodimers, in this case with the cis-retinoic acid receptor.

In conclusion, these data demonstrated the presence of a specific TR-binding site within a T₃-responsive region of the rat GLUT4 promoter and thus support the supposition that thyroid hormone acts directly to stimulate GLUT4 transcription in rat skeletal muscle. Moreover, characterization of a novel TR-binding site with low affinity suggests an additional mechanism by which the intrinsic activity and responsiveness of thyroid hormone regulated genes may be modulated.

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