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Molecular and Cellular Biology, April 2003, p. 2720-2732, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2720-2732.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Nucleoprotein Complex Containing Sp1, C/EBPß, and HMGI-Y Controls Human Insulin Receptor Gene Transcription

Daniela Foti, Rodolfo Iuliano, Eusebio Chiefari, and Antonio Brunetti*

Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore," Università degli Studi di Catanzaro "Magna Græcia," 88100 Catanzaro, Italy

Received 14 August 2002/ Returned for modification 16 October 2002/ Accepted 13 January 2003

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 ß (C/EBPß). Functional integrity of this nucleoprotein complex is required for full transactivation of the IR gene by Sp1 and C/EBPß in cells readily expressing IRs. We show that HMGI-Y physically interacts with Sp1 and C/EBPß 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/EBPß-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.

* Corresponding author. Mailing address: Cattedra di Endocrinologia, Policlinico "Mater Domini," Via T. Campanella 115, 88100 Catanzaro, Italy. Phone: 39 0961 712257. Fax: 39 0961 775373. E-mail: brunetti{at}unicz.it.

Molecular and Cellular Biology, April 2003, p. 2720-2732, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2720-2732.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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