Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation

Abstract

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPARγ induces hepatic steatosis, and liganded PPARγ promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPARγ function, transactivation, expression, and promoter activity. PPARγ transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPARγ ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPARγ-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1^−/− fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPARγ ligands of PPARγ and PPARγ-responsive genes, and cyclin D1^−/− mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPARγ in vivo. The inhibition of PPARγ function by cyclin D1 is a new mechanism of signal transduction cross talk between PPARγ ligands and mitogenic signals that induce cyclin D1.

ACKNOWLEDGMENTS

We thank R. Evans, V. Fantl, C. Glass, P. Sicinski, and M. Lazar for reagents and helpful discussion. We thank M. Caparas for assistance with the manuscript.

This work was supported in part by awards from the Susan Komen Breast Cancer Foundation, Breast Cancer Alliance Inc., R01CA70896, R01CA75503, R01CA86072, R01CA86071 (R.G.P.), R03AG20337 (C.A.), NIH CA06576 (P.N.), and R01DK55758 (P.E.S.). R.G.P was a recipient of the Irma T. Hirschl and Weil Caulier award and was the Diane Belfer Faculty Scholar in Cancer Research. M.D. was a recipient of the New York State mentored EMPIRE award. Work conducted at the Lombardi Cancer Center was supported by the NIH Cancer Center Core grant.