Cyclin D1 repression of peroxisome proliferator-activated receptor gamma 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 gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR gamma induces hepatic steatosis, and liganded PPAR gamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR gamma function, transactivation, expression, and promoter activity. PPAR gamma 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 PPAR gamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR gamma-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 PPAR gamma ligands of PPAR gamma and PPAR gamma-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 PPAR gamma in vivo. The inhibition of PPAR gamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR gamma ligands and mitogenic signals that induce cyclin D1.

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@article{Wang2003CyclinDR, title={Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation.}, author={Chenguang Wang and Nagarajan Pattabiraman and Jian Zhou and Maofu Fu and Toshiyuki Sakamaki and Chris Albanese and Zhiping Li and Kongming Wu and James Hulit and Peter Neumeister and Phyllis M. Novikoff and Michael D Brownlee and Philipp E Scherer and Joan G. Jones and Kathleen D. Whitney and Lawrence A. Donehower and Emily L. Harris and Thomas E. Rohan and David C. Johns and Richard G. Pestell}, journal={Molecular and cellular biology}, year={2003}, volume={23 17}, pages={6159-73} }