The serine/threonine phosphatase PPM1B (PP2Cβ) selectively modulates PPARγ activity

2013 ◽  
Vol 451 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Ismayil Tasdelen ◽  
Olivier van Beekum ◽  
Olena Gorbenko ◽  
Veerle Fleskens ◽  
Niels J. F. van den Broek ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Cellular Proteins ◽  
Peroxisome Proliferator ◽  
Serine Residue ◽  
Intact Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein

Reversible phosphorylation is a widespread molecular mechanism to regulate the function of cellular proteins, including transcription factors. Phosphorylation of the nuclear receptor PPARγ (peroxisome-proliferator-activated receptor γ) at two conserved serine residue (Ser112 and Ser273) results in an altered transcriptional activity of this transcription factor. So far, only a very limited number of cellular enzymatic activities has been described which can dephosphorylate nuclear receptors. In the present study we used immunoprecipitation assays coupled to tandem MS analysis to identify novel PPARγ-regulating proteins. We identified the serine/threonine phosphatase PPM1B [PP (protein phosphatase), Mg2+/Mn2+ dependent, 1B; also known as PP2Cβ] as a novel PPARγ-interacting protein. Endogenous PPM1B protein is localized in the nucleus of mature 3T3-L1 adipocytes where it can bind to PPARγ. Furthermore we show that PPM1B can directly dephosphorylate PPARγ, both in intact cells and in vitro. In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser112. Finally, we show that knockdown of PPM1B in 3T3-L1 adipocytes blunts the expression of some PPARγ target genes while leaving others unaltered. These findings qualify the phosphatase PPM1B as a novel selective modulator of PPARγ activity.

scholarly journals The Adipogenic Acetyltransferase Tip60 Targets Activation Function 1 of Peroxisome Proliferator-Activated Receptor γ

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1840-1849 ◽  
Author(s):  
Olivier van Beekum ◽  
Arjan B. Brenkman ◽  
Lars Grøntved ◽  
Nicole Hamers ◽  
Niels J. F. van den Broek ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Target Genes ◽  
Activation Function ◽  
Specific Gene ◽  
Chimeric Proteins ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
And Function ◽  
Interfering Rna

The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARγ is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARγ transcriptional activity. Using tandem mass spectrometry, we found that PPARγ and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARγ, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPARγ target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPARγ for its recruitment to PPARγ target genes. Importantly, we show that in common with disruption of PPARγ function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor.

scholarly journals Thioredoxin Binding Protein-2/Thioredoxin-Interacting Protein Is a Critical Regulator of Insulin Secretion and Peroxisome Proliferator-Activated Receptor Function

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1225-1234 ◽  
Author(s):  
Shin-ichi Oka ◽  
Eiji Yoshihara ◽  
Akiko Bizen-Abe ◽  
Wenrui Liu ◽  
Mutsumi Watanabe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Target Genes ◽  
Binding Protein ◽  
Dynamic Change ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Nutritional Transition ◽  
Coordinated Regulation

The feeding-fasting nutritional transition triggers a dynamic change in metabolic pathways and is a model for understanding how these pathways are mutually organized. The targeted disruption of the thioredoxin binding protein-2 (TBP-2)/thioredoxin-interacting protein (Txnip)/VDUP1 gene in mice results in lethality with hypertriglyceridemia and hypoglycemia during fasting. To investigate the molecular mechanism of the nutritional transition and the role of TBP-2, microarray analyses were performed using the liver of TBP-2−/− mice in the fed and fasted states. We found that the fasting-induced reduction in the expression of lipogenic genes targeted by insulin (SREBP-1), such as FASN and THRSP, was abolished in TBP-2−/− mice, and the expression of lipoprotein lipase is down-regulated, which was consistent with the lipoprotein profile. TBP-2−/− mice also exhibited enhanced glucose-induced insulin secretion and sensitivity. Another feature of the hepatic gene expression in fed TBP-2−/− mice was the augmented expression of peroxisome proliferator activated receptor (PPAR) target genes, such as CD36, FABP2, ACOT1, and FGF21, to regulate fatty acid consumption. In TBP-2−/− mice, PPARα expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPARα was attenuated. We also detected an increased expression of PPARγ coactivator-1α protein in fed TBP-2−/− mice. TBP-2 overexpression significantly inhibited PPARα-mediated transcriptional activity induced by a specific PPARα ligand in vitro. These results suggest that TBP-2 is a key regulator of PPARα expression and signaling, and coordinated regulation of PPARα and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition. TBP-2/Txnip is a key regulator of PPARα expression and signaling, and coordinated regulation of PPARα and insulin secretion by TBP-2/Txnip is crucial in fasting response.

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 The endocrine disruptor mono-(2-ethylhexyl)phthalate promotes adipocyte differentiation and induces obesity in mice

2012 ◽  
Vol 32 (6) ◽  
pp. 619-629 ◽  
Author(s):  
Chanjuan Hao ◽  
Xuejia Cheng ◽  
Hongfei Xia ◽  
Xu Ma
Keyword(s):  
Target Genes ◽  
Adipocyte Differentiation ◽  
Cell Model ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Ethylhexyl Phthalate

The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental ‘window’ contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.

SUMO modification selectively regulates transcriptional activity of peroxisome-proliferator-activated receptor γ in C2C12 myotubes

2010 ◽  
Vol 433 (1) ◽  
pp. 155-161 ◽  
Author(s):  
Sung Soo Chung ◽  
Byung Yong Ahn ◽  
Min Kim ◽  
Jun Ho Kho ◽  
Hye Seung Jung ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Transcriptional Activity ◽  
Target Genes ◽  
C2c12 Cells ◽  
C2c12 Myotubes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mouse Muscle ◽  
Fatty Acid Binding ◽  
Specific Protease

PPAR (peroxisome-proliferator-activated receptor) γ, a nuclear receptor, can be conjugated with SUMO (small ubiquitin-like modifier), which results in the negative regulation of its transcriptional activity. In the present study, we tested whether de-SUMOylation of PPARγ affects the expression of PPARγ target genes in mouse muscle cells and investigated the mechanism by which de-SUMOylation increases PPARγ transcriptional activity. We found that the SUMO-specific protease SENP2 [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1)-specific peptidase 2] effectively de-SUMOylates PPARγ–SUMO conjugates. Overexpression of SENP2 in C2C12 cells increased the expression of some PPARγ target genes, such as FABP3 (fatty-acid-binding protein 3) and CD36 (fatty acid translocase), both in the absence and presence of rosiglitazone. In contrast, overexpression of SENP2 did not affect the expression of another PPARγ target gene ADRP (adipose differentiation-related protein). De-SUMOylation of PPARγ increased ChIP (chromatin immunoprecipitation) of both a recombinant PPRE (PPAR-response element) and endogenous PPREs of the target genes CD36 and FABP3, but ChIP of the PPRE in the ADRP promoter was not affected by SENP2 overexpression. In conclusion, these results indicate that SENP2 de-SUMOylates PPARγ in myotubes, and de-SUMOylation of PPARγ selectively increases the expression of some PPARγ target genes.

scholarly journals SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

2016 ◽  
Vol 36 (7) ◽  
pp. 1180-1193 ◽  
Author(s):  
Nathan L. Price ◽  
Brandon Holtrup ◽  
Stephanie L. Kwei ◽  
Martin Wabitsch ◽  
Matthew Rodeheffer ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Target Genes ◽  
Adipocyte Differentiation ◽  
Regulatory Element ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promotingin vitroadipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precludingin vivoassessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along withSREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor γ (PPARγ) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.

scholarly journals MED14 Tethers Mediator to the N-Terminal Domain of Peroxisome Proliferator-Activated Receptor γ and Is Required for Full Transcriptional Activity and Adipogenesis

2010 ◽  
Vol 30 (9) ◽  
pp. 2155-2169 ◽  
Author(s):  
Lars Grøntved ◽  
Maria S. Madsen ◽  
Michael Boergesen ◽  
Robert G. Roeder ◽  
Susanne Mandrup
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Target Genes ◽  
Gene Activation ◽  
Proximal Promoter ◽  
Peroxisome Proliferator ◽  
Independent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Terminal Domain

ABSTRACT The Mediator subunit MED1/TRAP220/DRIP205/PBP interacts directly with many nuclear receptors and was long thought to be responsible for tethering Mediator to peroxisome proliferator-activated receptor (PPAR)-responsive promoters. However, it was demonstrated recently that PPARγ can recruit Mediator by MED1-independent mechanisms. Here, we show that target gene activation by ectopically expressed PPARγ and PPARα is independent of MED1. Consistent with this finding, recruitment of PPARγ, MED6, MED8, TATA box-binding protein (TBP), and RNA polymerase II (RNAPII) to the enhancer and proximal promoter of the PPARγ target gene Fabp4 is also independent of MED1. Using a small interfering RNA (siRNA)-based approach, we identify MED14 as a novel critical Mediator component for PPARγ-dependent transactivation, and we demonstrate that MED14 interacts directly with the N terminus of PPARγ in a ligand-independent manner. Interestingly, MED14 knockdown does not affect the recruitment of PPARγ, MED6, and MED8 to the Fabp4 enhancer but does reduce their occupancy of the Fabp4 proximal promoter. In agreement with the necessity of MED14 for PPARγ transcriptional activity, we show that knockdown of MED14 impairs adipogenesis of 3T3-L1 cells. Thus, MED14 constitutes a novel anchoring point between Mediator and the N-terminal domain of PPARγ that is necessary for functional PPARγ-mediated recruitment of Mediator and transactivation of PPARγ subtype-specific target genes.

scholarly journals MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema

2009 ◽  
Vol 23 (7) ◽  
pp. 975-988 ◽  
Author(s):  
Francine M. Gregoire ◽  
Fang Zhang ◽  
Holly J. Clarke ◽  
Thomas A. Gustafson ◽  
Dorothy D. Sears ◽  
...  
Keyword(s):  
Target Genes ◽  
Partial Agonist ◽  
Oral Glucose ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Sensitizer ◽  
Glucose Lowering ◽  
Ppar Γ ◽  
Primary Mouse

Abstract MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.

scholarly journals miR-139 Functions as An Antioncomir to Repress Glioma Progression Through Targeting IGF-1 R, AMY-1, and PGC-1β

2016 ◽  
Vol 16 (4) ◽  
pp. 497-511 ◽  
Author(s):  
Hong Wang ◽  
Xi Yan ◽  
Li-Ya Ji ◽  
Xi-Tuan Ji ◽  
Ping Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Epigenetic Modification ◽  
Negative Control ◽  
Peroxisome Proliferator ◽  
Insulin Like Growth Factor ◽  
Peroxisome Proliferator Activated Receptor

Gliomas are the most common primary malignant brain tumor with poor prognosis, characterized by a highly heterogeneous cell population, extensive proliferation, and migration. A lot of molecular mechanisms regulate gliomas development and invasion, including abnormal expression of oncogenes and variation of epigenetic modification. MicroRNAs could affect cell growth and functions. Several reports have demonstrated that miR-139 plays multifunctions in kinds of solid tumors through different pathways. However, the antitumor mechanisms of this miR-139 are not unveiled in detail. In this study, we not only validated the low expression level of miR-139 in glioma tissues and cell lines but also detected the effect of miR-139 on modulating gliomas proliferation and invasion both in vitro and in vivo. We identified insulin-like growth factor 1 receptor, associate of Myc 1, and peroxisome proliferator-activated receptor γ coactivator 1β as direct targets of miR-139 and the levels of them were all inversely correlated with miR-139 in gliomas. Insulin like growth factor 1 receptor promoted gliomas invasion through Akt signaling and increased proliferation in the peroxisome proliferator-activated receptor γ coactivator 1β-dependent way. Associate of Myc 1 also facilitated gliomas progression by activating c-Myc pathway. Overexpression of the target genes could retrieve the antitumor function of miR-139, respectively, in different degrees. The nude mice transplantation tumor experiment displayed that glioma cells stably expressed miR-139 growth much slower in vivo than the negative control cells. Taken together, these findings suggested miR-139 acted as a favorable factor against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new evidenced prognostic marker and therapeutic target for gliomas.

Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells

2018 ◽  
Vol 50 (08) ◽  
pp. 640-647 ◽  
Author(s):  
Michela Polidoro ◽  
Sandra Rotondi ◽  
Roberta Morace ◽  
Liliya Rostomyan ◽  
Alessandro Colapietro ◽  
...  
Keyword(s):  
Tumour Volume ◽  
Cell Number ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
Receptor Alpha ◽  
Aryl Hydrocarbon ◽  
High Concentrations ◽  
The Relationship

AbstractPeroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA – 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) – were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100–200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.

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