HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Costa, V Articles by Brunetti, A Search for Related Content PubMed PubMed Citation Articles by Costa, V Articles by Brunetti, A

Dipartimento di Medicina Sperimentale e Clinica ‘G. Salvatore’, Università di Catanzaro ‘Magna Græcia’, 88100 Catanzaro, Italy¹ Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, 20133 Milano, Italy² Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università di Napoli Federico II, e NOGEC-CEINGE, Biotecnologie Avanzate, 80131 Napoli, Italy

(Correspondence should be addressed to A Brunetti; Email: brunetti{at}unicz.it)

The peroxisome proliferator-activated receptor- (PPAR) is a member of the nuclear hormone receptor superfamily. Ligand activation of PPAR is associated with differentiation and inhibition of proliferation in the normal and malignant cells. Herein, we studied the effects of PPAR and the PPAR agonists thiazolidinediones (TZDs) on the insulin receptor (IR), a cell membrane tyrosine kinase receptor protein, whose role is of paramount importance in mediating the metabolic and growth-promoting effects of the peptide hormone insulin. Overexpression of the PPAR1 in human hepatocellular (HepG2) cells was associated with decreased IR gene transcription and protein expression levels, and these reductions were more evident in the presence of TZDs. Since no PPAR response elements were identified on the IR promoter, we postulated that PPAR adversely affects the IR gene transcription by perturbing the assembly and stability of the transcriptionally active multiprotein-DNA complex identified previously, which includes the high-mobility group A1 protein, the ubiquitously expressed transcription factor (Sp1), the CAAT enhancer-binding protein (C/EBPβ), and, in some cell lines, the developmentally regulated activator protein-2 (AP-2) transcription factor. Using glutathione S-transferase pull-down assays combined with electrophoretic mobility shift assay and chromatin immunoprecipitation, we demonstrated that by interacting with Sp1, C/EBPβ, and AP-2, PPAR can prevent Sp1/AP-2 protein–protein association and inhibit binding of Sp1 and C/EBPβ to DNA, thus reducing IR gene transcription. Our results demonstrate that IR is a new target gene of PPAR, and support a potential use of TZDs as anti-proliferative agents in selected neoplastic tissues overexpressing IRs.

This article has been cited by other articles:

				S. Han, X. Sun, J. D. Ritzenthaler, and J. Roman Fish Oil Inhibits Human Lung Carcinoma Cell Growth by Suppressing Integrin-Linked Kinase Mol. Cancer Res., January 1, 2009; 7(1): 108 - 117. [Abstract] [Full Text] [PDF]