scholarly journals Cyclin D3 Promotes Adipogenesis through Activation of Peroxisome Proliferator-Activated Receptor γ

2005 ◽  
Vol 25 (22) ◽  
pp. 9985-9995 ◽  
Author(s):  
David A. Sarruf ◽  
Irena Iankova ◽  
Anna Abella ◽  
Said Assou ◽  
Stéphanie Miard ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Receptor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Direct Interaction ◽  
Mitotic Division ◽  
Cyclin D3 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

ABSTRACT In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Our experiments reveal cyclin D3 acts as a ligand-dependent PPARγ coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPARγ activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPARγ target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.

scholarly journals Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation

2014 ◽  
Vol 53 (2) ◽  
pp. 191-200 ◽  
Author(s):  
Xiaoting Jiang ◽  
Xin Ye ◽  
Wei Guo ◽  
Hongyun Lu ◽  
Zhanguo Gao
Keyword(s):  
Insulin Sensitivity ◽  
Posttranslational Modifications ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Histone Deacetylase 3 ◽  
Protein Inhibition ◽  
Diet Induced Obesity ◽  
Exogenous Ligands

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation was required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for the improvement of insulin sensitivity.

scholarly journals PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sean R. Pyper ◽  
Navin Viswakarma ◽  
Yuzhi Jia ◽  
Yi-Jun Zhu ◽  
Joseph D. Fondell ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Coactivator ◽  
Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

scholarly journals Citrus ichangensisPeel Extract Exhibits Anti-Metabolic Disorder Effects by the Inhibition of PPARγand LXR Signaling in High-Fat Diet-Induced C57BL/6 Mouse

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaobo Ding ◽  
Shengjie Fan ◽  
Yan Lu ◽  
Yu Zhang ◽  
Ming Gu ◽  
...  
Keyword(s):  
Fatty Acid Synthase ◽  
Target Genes ◽  
Body Weight Gain ◽  
Density Lipoprotein ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Nutritional Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

Obesity is a common nutritional disorder associated with type 2 diabetes, cardiovascular diseases, dyslipidemia, and certain cancers. In this study, we investigated the effects ofCitrus ichangensispeel extract (CIE) in high-fat (HF) diet-induced obesity mice. Female C57BL/6 mice were fed a chow diet or an HF diet alone or supplemented with 1% w/w CIE for 8 weeks. We found that CIE treatment could lower blood glucose level and improve glucose tolerance. In the HF+CIE group, body weight gain, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels, and liver triglyceride (TG) and TC concentrations were significantly (P<0.05) decreased relative to those in the HF group. To elucidate the mechanism of CIE on the metabolism of glucose and lipid, related genes expression in liver were examined. In liver tissue, CIE significantly decreased the mRNA expression levels of peroxisome proliferator-activated receptorγ(PPARγ) and its target genes, such as fatty acid synthase (FAS) and acyl-CoA oxidase (ACO). Moreover, CIE also decreased the expression of liver X receptor (LXR)αandβwhich are involved in lipid and glucose metabolism. These results suggest that CIE administration could alleviate obesity and related metabolic disorders in HF diet-induced obesity mice through the inhibition of PPARγand LXR signaling.

Interleukin enhancer-binding factor 3 functions as a liver receptor homologue-1 co-activator in synergy with the nuclear receptor co-activators PRMT1 and PGC-1α

2011 ◽  
Vol 437 (3) ◽  
pp. 531-540 ◽  
Author(s):  
Masae Ohno ◽  
Jun Komakine ◽  
Eiko Suzuki ◽  
Makoto Nishizuka ◽  
Shigehiro Osada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Gene Encoding ◽  
Peroxisome Proliferator Activated Receptor ◽  
Binding Factor ◽  
Protein Arginine Methyltransferase 1

LRH-1 (liver receptor homologue-1), a transcription factor and member of the nuclear receptor superfamily, regulates the expression of its target genes, which are involved in bile acid and cholesterol homoeostasis. However, the molecular mechanisms of transcriptional control by LRH-1 are not completely understood. Previously, we identified Ku80 and Ku70 as LRH-1-binding proteins and reported that they function as co-repressors. In the present study, we identified an additional LRH-1-binding protein, ILF3 (interleukin enhancer-binding factor 3). ILF3 formed a complex with LRH-1 and the other two nuclear receptor co-activators PRMT1 (protein arginine methyltransferase 1) and PGC-1α (peroxisome proliferator-activated receptor γ co-activator-1α). We demonstrated that ILF3, PRMT1 and PGC-1α were recruited to the promoter region of the LRH-1-regulated SHP (small heterodimer partner) gene, encoding one of the nuclear receptors. ILF3 enhanced SHP gene expression in co-operation with PRMT1 and PGC-1α through the C-terminal region of ILF3. In addition, we found that the small interfering RNA-mediated down-regulation of ILF3 expression led to a reduction in the occupancy of PGC-1α at the SHP promoter and SHP expression. Taken together, our results suggest that ILF3 functions as a novel LRH-1 co-activator by acting synergistically with PRMT1 and PGC-1α, thereby promoting LRH-1-dependent gene expression.

scholarly journals Keratin 19 regulates cell cycle pathway and sensitivity of breast cancer cells to CDK inhibitors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pooja Sharma ◽  
Sarah Alsharif ◽  
Karina Bursch ◽  
Swetha Parvathaneni ◽  
Dimitrios G. Anastasakis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Structural Integrity ◽  
Cyclin D3 ◽  
Cdk Inhibitors ◽  
Keratin 19

Abstract Keratin 19 (K19) belongs to the keratin family of proteins, which maintains structural integrity of epithelia. In cancer, K19 is highly expressed in several types where it serves as a diagnostic marker. Despite the positive correlation between higher expression of K19 in tumor and worse patient survival, the role of K19 in breast cancer remains unclear. Therefore, we ablated K19 expression in MCF7 breast cancer cells and found that K19 was required for cell proliferation. Transcriptome analyses of KRT19 knockout cells identified defects in cell cycle progression and levels of target genes of E2F1, a key transcriptional factor for the transition into S phase. Furthermore, proper levels of cyclin dependent kinases (CDKs) and cyclins, including D-type cyclins critical for E2F1 activation, were dependent on K19 expression, and K19-cyclin D co-expression was observed in human breast cancer tissues. Importantly, K19 interacts with cyclin D3, and a loss of K19 resulted in decreased protein stability of cyclin D3 and sensitivity of cells towards CDK inhibitor-induced cell death. Overall, these findings reveal a novel function of K19 in the regulation of cell cycle program and suggest that K19 may be used to predict the efficacy of CDK inhibitors for treatments of breast cancer.

scholarly journals Rhein Reduces Fat Weight indb/dbMouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPARγSignaling

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yu Zhang ◽  
Shengjie Fan ◽  
Na Hu ◽  
Ming Gu ◽  
Chunxiao Chu ◽  
...  
Keyword(s):  
Target Genes ◽  
Fasting Blood Glucose ◽  
Peroxisome Proliferator ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Rheum Palmatum ◽  
Diet Induced Obesity ◽  
Blood Glucose Levels ◽  
Underlying Mechanisms

Rheum palmatumhas been used most frequently in the weight-reducing formulae in traditional Chinese medicine. However, the components ofRheum palmatumthat play the antiobesity role are still uncertain. Here, we tested the weight-reducing effect of two majorRheum palmatumcompounds ondb/dbmouse. We found that rhein (100 mg kg−1 day−1), but not emodin, reduced the fat weight indb/dbmouse. Using diet-induced obese (DIO) C57BL/6 mice, we identified that rhein blocked high-fat diet-induced obesity, decreased fat mass and the size of white and brown adipocytes, and lowered serum cholesterol, LDL cholesterol, and fasting blood glucose levels in the mice. To elucidate the underlying mechanisms, we used reporter assay and gene expression analysis and found that rhein inhibited peroxisome proliferator-activated receptorγ(PPARγ) transactivity and the expression of its target genes, suggesting that rhein may act as a PPARγantagonist. Our data indicate that rhein may be a promising choice for antiobesity therapy.

scholarly journals Definition of the Molecular Basis for Estrogen Receptor-Related Receptor-α-Cofactor Interactions

2007 ◽  
Vol 21 (1) ◽  
pp. 62-76 ◽  
Author(s):  
Stéphanie Gaillard ◽  
Mary A. Dwyer ◽  
Donald P. McDonnell
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Activation Function ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hormone Response Elements ◽  
Phage Libraries ◽  
Definition Of

Abstract Estrogen receptor-related receptor-α (ERRα) is an orphan nuclear receptor that does not appear to require a classical small molecule ligand to facilitate its interaction with coactivators and/or hormone response elements within target genes. Instead, the apo-receptor is capable of interacting in a constitutive manner with coactivators that stimulate transcription by acting as protein ligands. We have screened combinatorial phage libraries for peptides that selectively interact with ERRα to probe the architecture of the ERRα-coactivator pocket. In this manner, we have uncovered a fundamental difference in the mechanism by which this receptor interacts with peroxisome proliferator-activated receptor-γ coactivator-1α, as compared with members of the steroid receptor coactivator subfamily of coactivators. Our findings suggest that it may be possible to develop ERRα ligands that exhibit different pharmacological activities as a consequence of their ability to differentially regulate coactivator recruitment. In addition, these findings have implications beyond ERRα because they suggest that subtle alterations in the structure of the activation function-2 pocket within any nuclear receptor may enable differential recruitment of coactivators, an observation of notable pharmaceutical importance.

scholarly journals EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yiming He ◽  
Mingxi Gan ◽  
Yanan Wang ◽  
Tong Huang ◽  
Jianbin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Potential Role ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Phosphorylation Site ◽  
Promoter Regions ◽  
Cycle Progression

AbstractGrainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

scholarly journals New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Daniela P. Foti ◽  
Francesco Paonessa ◽  
Eusebio Chiefari ◽  
Antonio Brunetti
Keyword(s):  
Insulin Receptor ◽  
Target Genes ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Peptide Hormone ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Preclinical Research ◽  
Peroxisome Proliferator Activated Receptor ◽  
Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

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