title: 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.
authors.affiliation: Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007, USA.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
authors.forename: Jian Nian
authors.initials: JN
authors.lastname: Zhou
authors.forename: Maofu
authors.initials: M
authors.lastname: Fu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakamaki
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: James
authors.initials: J
authors.lastname: Hulit
authors.forename: Peter
authors.initials: P
authors.lastname: Neumeister
authors.forename: Phyllis M
authors.initials: PM
authors.lastname: Novikoff
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Joan G
authors.initials: JG
authors.lastname: Jones
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Whitney
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.forename: Emily L
authors.initials: EL
authors.lastname: Harris
authors.forename: Thomas
authors.initials: T
authors.lastname: Rohan
authors.forename: David C
authors.initials: DC
authors.lastname: Johns
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D019938:Cyclin D1 / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D012016:Reference Values; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D019938:Cyclin D1; D004441:Ecdysterone; C008999:ponasterone A