A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription.
HMGI-Y is an architectural transcription factor that regulates gene expression in vivo by controlling the formation of stereospecific multiprotein complexes on the AT-rich regions of certain gene promoters. Recently, we demonstrated that HMGI-Y is required for proper transcription of the insulin receptor (IR) gene. Here we provide evidence that transcriptional ... activation of the human IR promoter requires the assembly of a transcriptionally active multiprotein-DNA complex which includes, in addition to HMGI-Y, the ubiquitously expressed transcription factor Sp1 and the CCAAT-enhancer binding protein beta (C/EBP beta). Functional integrity of this nucleoprotein complex is required for full transactivation of the IR gene by Sp1 and C/EBP beta in cells readily expressing IRs. We show that HMGI-Y physically interacts with Sp1 and C/EBP beta and facilitates the binding of both factors to the IR promoter in vitro. Furthermore, HMGI-Y is needed for transcriptional synergism between these factors in vivo. Repression of HMGI-Y function adversely affects both Sp1- and C/EBP beta-induced transactivation of the IR promoter. Together, these findings demonstrate that HMGI-Y plays significant molecular roles in the transcriptional activities of these factors in the context of the IR gene and provide concordant support for the hypothesis that, in affected individuals, a putative defect in these nuclear proteins may cause decreased IR expression with subsequent impairment of insulin signaling and action.
Mesh Terms:
3T3 Cells, Animals, Base Sequence, Binding Sites, CCAAT-Enhancer-Binding Protein-beta, Cell Line, Cell Transformation, Viral, DNA, Diabetes Mellitus, HMGA1a Protein, Herpesvirus 4, Human, Humans, Mice, Models, Biological, Nucleoproteins, Promoter Regions, Genetic, Receptor, Insulin, Recombinant Proteins, Signal Transduction, Sp1 Transcription Factor, Transcription, Genetic
3T3 Cells, Animals, Base Sequence, Binding Sites, CCAAT-Enhancer-Binding Protein-beta, Cell Line, Cell Transformation, Viral, DNA, Diabetes Mellitus, HMGA1a Protein, Herpesvirus 4, Human, Humans, Mice, Models, Biological, Nucleoproteins, Promoter Regions, Genetic, Receptor, Insulin, Recombinant Proteins, Signal Transduction, Sp1 Transcription Factor, Transcription, Genetic
Mol. Cell. Biol.
Date: Apr. 01, 2003
PubMed ID: 12665574
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