Critical Role of the HMGI(Y) Proteins in Adipocytic Cell Growth and Differentiation

doi:10.1128/MCB.21.7.2485-2495.2001

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Molecular and Cellular Biology, April 2001, p. 2485-2495, Vol. 21, No. 7
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.7.2485-2495.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Critical Role of the HMGI(Y) Proteins in Adipocytic Cell Growth and Differentiation

Rosa Marina Melillo,¹ Giovanna Maria Pierantoni,¹ Stefania Scala,¹ Sabrina Battista,¹ Monica Fedele,¹ Antonella Stella,² Maria Cristina De Biasio,³ Gennaro Chiappetta,³ Vincenzo Fidanza,⁴ Gianluigi Condorelli,⁴ Massimo Santoro,¹ Carlo M. Croce,⁴ Giuseppe Viglietto,³ and Alfredo Fusco²^,^*

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologiae Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli,¹ and Istituto Nazionale dei Tumori Fondazione Senatore Pascale,³ 80131 Naples, and Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Università degli Studi di Catanzaro, 88100 Catanzaro,² Italy, and Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107⁴

Received 2 June 2000/Returned for modification 31 July 2000/Accepted 11 January 2001

The high-mobility group I (HMGI) nonhistone chromosomal proteins HMGI(Y) and HMGI-C have been implicated in defining chromatinstructure and in regulating the transcription of several genes.These proteins have been implicated in adipocyte homeostasis:a severe deficiency of fat tissue is found in mice with targeteddisruption of the HMGI-C locus, and lipomagenesis in humans isfrequently associated with somatic mutations of HMGI genes. Theaim of this study was to examine the role of HMGI(Y) proteinsin adipocytic cell growth and differentiation. First, we foundthat differentiation of the preadipocytic 3T3-L1 cell line causedearly induction of HMGI(Y) gene expression. Suppression of HMGI(Y)expression by antisense technology dramatically increased thegrowth rate and impaired adipocytic differentiation in these cells.The process of adipogenic differentiation involves the interplayof several transcription factors, among which is the CCAAT/enhancer-bindingprotein (C/EBP) family of proteins. These factors are requiredfor the transcriptional activation of adipocyte-specific genes.We also tested the hypothesis that HMGI(Y) might participate intranscriptional control of adipocyte-specific promoters. We foundthat HMGI(Y) proteins bind C/EBP $beta$ in vivo and in vitro. Furthermore,we show that HMGI(Y) strongly potentiates the capacity of C/EBP $beta$ to transactivate the leptin promoter, an adipose-specific promoter.Taken together, these results indicate that the HMGI(Y) proteinsplay a critical role in adipocytic cell growth anddifferentiation.

^* Corresponding author. Mailing address: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina eChirurgia, Via Pansini, 5, 80131 Naples, Italy. Phone: 39 0817463056. Fax: 39 081 7463037 or 7701016. E-mail: afusco{at}napoli.com.

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