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Departments of Medicine (J.-L.Z., C.-I.P., K.-w.M.L., L.S.P.) and Microbiology-Immunology (G.-j.W.), Emory University School of Medicine, Department of Biology, Morris Brown College (E.H.), Atlanta, Georgia 30322
Address all correspondence and requests for reprints to: Lawrence S. Phillips, M.D., Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, 1639 Pierce Drive, Woodruff Memorial Research Building, Room 1301, Atlanta, Georgia 30322. E-mail: medlsp{at}emory.edu
In the liver, most insulin-like growth factor I (IGF-I) transcripts originate in exon 1, where important cis-regulatory regions are located downstream from the major transcription initiation sites. Within these regions, we have attempted to identify sequences which are involved in the decrease in IGF-I gene transcription associated with diabetes mellitus. The function of different genomic templates was assessed by in vitro transcription, which revealed a consistent 50–80% decrease in the activity of nuclear extracts from streptozotocin-diabetic as compared with normal rats. The disparity in transcriptional activity between normal and diabetic nuclear extracts was reduced with templates containing 11-bp mutations within DNase I protected regions III or V (+42 and +129 bp, respectively, from the major transcription initiation site), but a mutation between regions IV and V had little effect. Within region III, gel mobility shift analysis and methylation interference studies indicated that DNA-protein interactions involve a GCGC core sequence. In region V, gel mobility shift studies and uracil interference analysis revealed interactions involving a TTAT core. While gel mobility shift analysis and transient transfection studies indicate that the GCGC core sequence in region III recognizes C/EBP, the AT-rich sequence in region V is likely to recognize a protein with homeodomain characteristics. Identification of the nuclear factor(s) interacting with regions III and V, downstream from exon 1 initiation sites, will be important for understanding the mechanism of reduced IGF-I gene transcription due to diabetes mellitus.
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