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Transcriptional regulation of human insulin receptor gene by the high-mobility group protein HMGI(Y)

ANTONIO BRUNETTI^*1, GUIDALBERTO MANFIOLETTI, EUSEBIO CHIEFARI^*, IRA D. GOLDFINE and DANIELA FOTI^§

^* Dipartimento di Medicina Sperimentale e Clinica ‘G. Salvatore’, Cattedra di Endocrinologia, Università degli Studi di Catanzaro ‘Magna Græcia’, Catanzaro, Italy;
Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, Università degli Studi di Trieste, Trieste, Italy;
Department of Medicine, Division of Diabetes and Endocrine Research, Mount Zion Medical Center, University of California San Francisco, San Francisco, California 94120, USA; and
^§ Dipartimento di Medicina Sperimentale e Clinica ‘G. Salvatore’, Cattedra di Medicina Interna, Università degli Studi di Catanzaro ‘Magna Græcia’, Catanzaro, Italy

¹Correspondence: Cattedra di Endocrinologia, Policlinico ‘Mater Domini’, Via T. Campanella 115, 88100 Catanzaro, Italy. E-mail: antonio.brunetti{at}tin.it

We have previously identified two closely related nuclear binding proteins that specifically interact with two unique functional AT-rich sequences of the 5' regulatory region of the human insulin receptor gene. Expression of these nuclear binding proteins increases during myocyte and adipocyte differentiation, and in other tissues appears to correlate with insulin receptor content. We have hypothesized, therefore, that insulin receptor expression in the insulin target tissues is regulated at least in part by these nuclear proteins. Here we show data on purification and biochemical characterization of these DNA binding proteins. Using a conventional chromatographic purification procedure combined with electrophoresis mobility shift assay and immunoblot analyses, a unique 15 kDa protein, either identical to or highly related to the architectural transcription factor HMGI(Y), has now been identified, suggesting an essential role for HMGI(Y) in regulating insulin receptor gene transcription. Direct evidence of HMGI(Y) insulin receptor promoter interactions is provided by functional analysis with the CAT reporter gene and by hormone binding studies in cells expressing HMGI(Y) antisense RNA. In these experiments, antisense HMGI(Y) specifically inhibits insulin receptor promoter function and insulin receptor protein expression, indicating that HMGI(Y) is required for proper transcription of insulin receptor gene. Moreover, our data consistently support the hypothesis that a putative defect in this nuclear binding protein may cause insulin receptor dysfunction with subsequent impairment of insulin signaling and action.—Brunetti, A., Manfioletti, G., Chiefari, E., Goldfine, I. D., Foti, D. Transcriptional regulation of human insulin receptor gene by the high-mobility group protein HMGI(Y).

Key Words: insulin receptor promoter • transcription factors • CAT reporter gene

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