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Selected Publication:
Wang, C; Pattabiraman, N; Zhou, JN; Fu, M; Sakamaki, T; Albanese, C; Li, Z; Wu, K; Hulit, J; Neumeister, P; Novikoff, PM; Brownlee, M; Scherer, PE; Jones, JG; Whitney, KD; Donehower, LA; Harris, EL; Rohan, T; Johns, DC; Pestell, RG.
Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation.
Mol Cell Biol. 2003; 23(17):6159-6173
Doi: 10.1128%2FMCB.23.17.6159-6173.2003
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- Co-authors Med Uni Graz
- Neumeister Peter
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- 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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