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

Abstract

The high-mobility group I (HMGI) nonhistone chromosomal proteins HMGI(Y) and HMGI-C have been implicated in defining chromatin structure 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 targeted disruption of the HMGI-C locus, and lipomagenesis in humans is frequently associated with somatic mutations of HMGI genes. The aim of this study was to examine the role of HMGI(Y) proteins in adipocytic cell growth and differentiation. First, we found that differentiation of the preadipocytic 3T3-L1 cell line caused early induction of HMGI(Y) gene expression. Suppression of HMGI(Y) expression by antisense technology dramatically increased the growth rate and impaired adipocytic differentiation in these cells. The process of adipogenic differentiation involves the interplay of several transcription factors, among which is the CCAAT/enhancer-binding protein (C/EBP) family of proteins. These factors are required for the transcriptional activation of adipocyte-specific genes. We also tested the hypothesis that HMGI(Y) might participate in transcriptional control of adipocyte-specific promoters. We found that HMGI(Y) proteins bind C/EBPβ in vivo and in vitro. Furthermore, we show that HMGI(Y) strongly potentiates the capacity of C/EBPβ to transactivate the leptin promoter, an adipose-specific promoter. Taken together, these results indicate that the HMGI(Y) proteins play a critical role in adipocytic cell growth and differentiation.

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Retraction for Melillo et al., “Critical Role of the HMGI(Y) Proteins in Adipocytic Cell Growth and Differentiation”

ACKNOWLEDGMENTS

This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Progetto Finalizzato Biotecnologie of Consiglio Nazionale delle Ricerche. G.M.P. and A.S. are supported by a Fondazione Italiana per la Ricerca sul Cancro (FIRC) fellowship.

We are grateful to Jean Gilder for revising and editing the text. We are indebted to D. Thanos for the HMGI(Y) deletion mutants and to M. Reitman for the p(−762)ob-luc, p(− 161)ob-luc, and m52 plasmids. We also thank Fernando Sferratore for excellent technical assistance.