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 ␥ (PPAR␥) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR␥ induces hepatic steatosis, and liganded PPAR␥ promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR␥ function, transactivation, expression, and promoter activity. PPAR␥ 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 ( The cyclin-dependent kinase holoenzymes are a family of serine/threonine kinases that play a pivotal role in controlling progression through the cell cycle (38,47). Dysregulation of the cell cycle control apparatus is an almost uniform aberration in tumorigenesis (48). The cyclins encode regulatory subunits of the kinases which phosphorylate specific proteins, including the retinoblastoma (pRB) protein, to promote transition through specific cell cycle checkpoints (47, 57). Cyclin D1 plays a pivotal role in G 1 /S phase cell cycle progression in fibroblasts and is rate limiting in growth factor-or estrogen-induced mammary epithelial cell proliferation (29, 67). Cyclin D1 overexpression is found in Ͼ30% of human breast cancers, correlating with poor prognosis (23). Several different oncogenic signals induce cyclin D1 expression, including mutations of the Ras and Wnt/APC/␤-catenin pathway (2, 49). Mammary-targeted expression of cyclin D1 is sufficient for the induction of mammary adenocarcinoma, and cyclin D1 Ϫ/Ϫ mice are resistant to ErbB2-induced tumorigenesis (53,64).In addition to binding cyclin-dependent kinases 4 and 6 (cdk4 and cdk6) and pRB, cyclin D1 forms physical associations with P/CAF (p300/CBP-associated factor), Myb, MyoD, and the cyclin D1 myb-like binding protein (DMP1) (16,20,31,39). Binding of cyclin D1 to the estrogen receptor alpha (ER␣) enhances ligand-independent reporter gene activity, and liganded androgen receptor reporter gene activity is inhibited by cyclin D1 (33, 39, 68). The in vivo or genetic evidence indicating a requirement for cyclin D1 in nuclear receptor function remained to be determined. The peroxisome proliferator-activator receptors, including PPAR␣, PPAR␥, and PPAR␦, are ligand-activated nuclear receptors (42). Their modular structure resembles those of other nuclear hormone receptors with N-terminal AF-1, a DNA binding domain, and a carboxyl-terminal ligand-binding domain (LBD). PPAR␥ was cloned as a transcription factor involved in fat cell differentiation and is required for the induction of adipocyte differentiation (41, 51). Adenoviral delivery of PPAR␥ to the livers of mice induces hepatic steatosis, consistent with an important role for PPAR␥ in hepatocellular lipid biosynthesis (65). The PPAR␥ ligands include eicosanoids, such as 15-deoxy-⌬12,14-prostaglandin J2 (15d-PGJ 2 ), and synthetic ligands of the thiazolidinedione (TZD) class. PPAR␥ ...

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

“…To support a functional link between La expression, CCND1 expression and cell proliferation, we compared the proliferation rate of La-depleted and control-treated immortalized mouse embryonic fibroblast (MEF) cells originating from CCND1 knockout mice (MEF CCND1À/À 3T3 cells (Albanese et al, 1999;Wang et al, 2003)). In contrast to all other tested cell lines, the proliferation rate of La-depleted MEF CCND1À/À was not reduced (Figure 5a).…”

“…New HeLa cell cultures were established every 2-3 months. MEF CCND1À/À 3T3 cells (Albanese et al, 1999;Wang et al, 2003) were kindly provided by RG Pestell (Thomas Jefferson University, Philadelphia, PA, USA). All cells were cultured in complete DMEM plus 10% fetal bovine serum.…”

Cyclin D3 action in androgen receptor regulation and prostate cancer

“…In specific cell types, cyclin D1 is found in association with the estrogen receptor a, thyroid hormone receptor, peroxisome proliferatoractivated receptor-g and the androgen receptor (AR) (Neuman et al, 1997;Zwijsen et al, 1998;Knudsen et al, 1999;Reutens et al, 2001;Lin et al, 2002;Petre et al, 2002;Petre-Draviam et al, 2003;Wang et al, 2003;Burd et al, 2005). With estrogen receptor, cyclin D1 can potentiate receptor activity independently of ligand and CDK4-kinase activity (Neuman et al, 1997), through formation of a ternary complex with estrogen receptor a and P/CAF, thereby altering chromatin structure to facilitate gene transcription (McMahon et al, 1999).…”

“…Lastly, cyclins D1 and D3 differentially modulate transcription factor activity. Cyclin D1 inhibits peroxisome proliferator-activated receptor-g independently of CDK; however, cyclin D3 enhances peroxisome proliferator-activated receptor-g action through CDK-dependent mechanisms (Wang et al, 2003;Sarruf et al, 2005). Recent evidence also suggests that maintenance of the liver is mediated, in part, through cyclin D3/CDK4-dependent modulation of C/EBPa/b.…”

Structural Basis for the Modulation of CDK-Dependent/Independent Activity of Cyclin D1

“…1A and 1C) permits an enhanced specificity toward a particular cyclin-CDK complex. Secondly, in addition to its kinase-activating function, cyclin D1 exhibits also CDK-independent roles by binding and modulating activity of several transcription factors like estrogen receptor, [28][29][30] thyroid hormone receptor, peroxisome proliferator gamma, 31 androgen receptor, and many others (for a review, see ref. 32).…”