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.
Foti
Daniela
D
Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università degli Studi di Catanzaro Magna Graecia, 88100 Catanzaro, Italy.
Iuliano
Rodolfo
R
Chiefari
Eusebio
E
Brunetti
Antonio
A
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002472:Cell Transformation, Viral; D004247:DNA / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D004854:Herpesvirus 4, Human; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009698:Nucleoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; D009698:Nucleoproteins; D011994:Recombinant Proteins; D016329:Sp1 Transcription Factor; D025741:HMGA1a Protein; D004247:DNA; D011972:Receptor, Insulin