scholarly journals Repression of Transcription Factor AP-2 Alpha by Peroxisome Proliferator Activated Receptor Gamma Reveals a Novel Transcriptional Circuit in basal-squamous Bladder Cancer

2018 ◽  
Author(s):  
Hironobu Yamashita ◽  
Yuka Imamura Kawasawa ◽  
Lauren Shuman ◽  
Zongyu Zheng ◽  
Truc Tran ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Molecular Subtype ◽  
Distant Recurrence ◽  
Peroxisome Proliferator ◽  
Rna Seq ◽  
Squamous Differentiation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

AbstractThe discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to “plasticity” of molecular subtype during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified. As PPARγ has been repeatedly implicated in the luminal subtype of bladder cancer, we hypothesized inactivation of this transcriptional master regulator during progression results in increased expression of basal-squamous specific transcription factors (TFs) which act to drive aggressive behavior. We initiated a pharmacologic and RNA-seq-based screen to identify PPARγ-repressed, basal-squamous specific TFs. Hierarchical clustering of RNA-seq data following treatment of a panel of human bladder cancer cell lines with a PPARγ agonist identified a number of TFs regulated by PPARγ activation, several of which are implicated in urothelial and squamous differentiation. One PPARγ-repressed TF implicated in squamous differentiation identified is Transcription Factor Activating Protein 2 alpha (TFAP2A). We show TFAP2A and its paralog TFAP2C are overexpressed in basal-squamous bladder cancer and in squamous areas of cystectomy samples, and that overexpression is associated with increased lymph node metastasis and distant recurrence, respectively. Biochemical analysis confirmed the ability of PPARγ activation to repress TFAP2A, while PPARγ antagonist studies indicate the requirement of a functional receptor. In vivo tissue recombination studies show TFAP2A and TFAP2C promote tumor growth in line with the aggressive nature of basal-squamous bladder cancer. Our findings suggest PPARγ inactivation, as well as TFAP2A and TFAP2C overexpression cooperate with other TFs to promote the basal-squamous transition.

scholarly journals Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer

Oncogenesis ◽  
2019 ◽  
Vol 8 (12) ◽  
Author(s):  
Hironobu Yamashita ◽  
Yuka I. Kawasawa ◽  
Lauren Shuman ◽  
Zongyu Zheng ◽  
Truc Tran ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Molecular Subtype ◽  
Distant Recurrence ◽  
Rna Seq ◽  
Squamous Differentiation ◽  
Promote Tumor Growth ◽  
Risk Patients ◽  
Tissue Recombination

AbstractThe discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to regional differences in molecular subtype within the tumor, as well as during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified. As PPARɣ has been repeatedly implicated in the luminal subtype of bladder cancer, we hypothesized inactivation of this transcriptional master regulator during progression results in increased expression of basal-squamous specific transcription factors (TFs) which act to drive aggressive behavior. We initiated a pharmacologic and RNA-seq-based screen to identify PPARɣ-repressed, basal-squamous specific TFs. Hierarchical clustering of RNA-seq data following treatment of three human bladder cancer cells with a PPARɣ agonist identified a number of TFs regulated by PPARɣ activation, several of which are implicated in urothelial and squamous differentiation. One PPARɣ-repressed TF implicated in squamous differentiation identified is Transcription Factor Activating Protein 2 alpha (TFAP2A). We show TFAP2A and its paralog TFAP2C are overexpressed in basal-squamous bladder cancer and in squamous areas of cystectomy samples, and that overexpression is associated with increased lymph node metastasis and distant recurrence, respectively. Biochemical analysis confirmed the ability of PPARɣ activation to repress TFAP2A, while PPARɣ antagonist and PPARɣ siRNA knockdown studies indicate the requirement of a functional receptor. In vivo tissue recombination studies show TFAP2A and TFAP2C promote tumor growth in line with the aggressive nature of basal-squamous bladder cancer. Our findings suggest PPARɣ inactivation, as well as TFAP2A and TFAP2C overexpression cooperate with other TFs to promote the basal-squamous transition during tumor progression.

scholarly journals Peroxisome proliferator-activated receptor γ and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles

2008 ◽  
Vol 99 (01) ◽  
pp. 86-95 ◽  
Author(s):  
Sherry L Spinelli ◽  
Stephen J Pollock ◽  
Thomas I Murant ◽  
Jamie J O’Brien ◽  
Neil Blumberg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Platelet Activation ◽  
Human Platelets ◽  
Retinoid X Receptor ◽  
Complex Spectrum ◽  
Peroxisome Proliferator ◽  
Monocytic Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
New Findings

SummaryPeroxisome proliferator-activated receptor γ (PPARγ) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARγ and that PPARγ ligands blunt platelet activation. To further understand the nature of PPARγ in platelets, we determined the platelet PPARγ isoform(s) and investigated the fate of PPARγ following platelet activation. Our studies demonstrated that human platelets contain only the PPARγ1 isoform and after activation with thrombin, TRAP, ADP or collagen PPARγ is released from internal stores. PPARγ release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARγ was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARγ and RXR were microparticle associated and the released PPARγ/RXR complex retained DNA-binding ability. Additionally, a monocytic cell line, THP-1, is capable of internalizing PMPs. Further investigation following treatment of these cells with the PPARγ agonist, rosiglitazone and PMPs revealed a possible transcellular mechanism to attenuate THP-1 activation. These new findings are the first to demonstrate transcription factor release from platelets, revealing the complex spectrum of proteins expressed and expelled from platelets, and suggests that platelet PPARγ has an undiscovered role in human biology.

scholarly journals Ligand-Activated Peroxisome Proliferator Activated Receptor γ Alters Placental Morphology and Placental Fatty Acid Uptake in Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3625-3634 ◽  
Author(s):  
W. Timothy Schaiff ◽  
F. F. (Russ) Knapp ◽  
Yaacov Barak ◽  
Tal Biron-Shental ◽  
D. Michael Nelson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Altered Expression ◽  
Pparγ Agonist

The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) is essential for murine placental development. We previously showed that activation of PPARγ in primary human trophoblasts enhances the uptake of fatty acids and alters the expression of several proteins associated with fatty acid trafficking. In this study we examined the effect of ligand-activated PPARγ on placental development and transplacental fatty acid transport in wild-type (wt) and PPARγ+/− embryos. We found that exposure of pregnant mice to the PPARγ agonist rosiglitazone for 8 d (embryonic d 10.5–18.5) reduced the weights of wt, but not PPARγ+/− placentas and embryos. Exposure to rosiglitazone reduced the thickness of the spongiotrophoblast layer and the surface area of labyrinthine vasculature, and altered expression of proteins implicated in placental development. The expression of fatty acid transport protein 1 (FATP1), FATP4, adipose differentiation related protein, S3-12, and myocardial lipid droplet protein was enhanced in placentas of rosiglitazone-treated wt embryos, whereas the expression of FATP-2, -3, and -6 was decreased. Additionally, rosiglitazone treatment was associated with enhanced accumulation of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid in the placenta, but not in the embryos. These results demonstrate that in vivo activation of PPARγ modulates placental morphology and fatty acid accumulation.

scholarly journals Structural basis of altered potency and efficacy displayed by a major in vivo metabolite of the anti-diabetic PPARγ drug pioglitazone

2018 ◽  
Author(s):  
Sarah A. Mosure ◽  
Jinsai Shang ◽  
Richard Brust ◽  
Jie Zheng ◽  
Patrick R. Griffin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Activation Function ◽  
Structural Basis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exchange Mass Spectrometry ◽  
Pparγ Agonist ◽  
A Cell ◽  
And Function

ABSTRACTThe thiazolidinedione (TZD) pioglitazone (Pio) is an FDA-approved drug for type 2 diabetes mellitus that binds and activates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). Although TZDs have potent antidiabetic effects, they also display harmful side effects that have necessitated a better understanding of their mechanisms of action. In particular, little is known about the effect of in vivo TZD metabolites on the structure and function of PPARγ. Here, we present a structure-function comparison of Pio and a major in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in coregulator recruitment assays compared to Pio. To determine the structural basis of these findings, we solved an X-ray crystal structure of PioOH bound to PPARγ ligand-binding domain (LBD) and compared it to a published Pio-bound crystal structure. PioOH exhibited an altered hydrogen bonding network that could underlie its reduced affinity and potency compared to Pio. Solution-state structural analysis using NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PioOH stabilizes the PPARγ activation function-2 (AF-2) coactivator binding surface better than Pio. In support of AF-2 stabilization, PioOH displayed stabilized coactivator binding in biochemical assays and better transcriptional efficacy (maximal transactivation response) in a cell-based assay that reports on the activity of the PPARγ LBD. These results, which indicate that Pio hydroxylation affects both its potency and efficacy as a PPARγ agonist, contribute to our understanding of PPARγ-binding drug metabolite interactions and may assist in future PPARγ drug design efforts.

scholarly journals Comprehensive analysis of PPARγ agonist activities of stereo-, regio-, and enantio-isomers of hydroxyoctadecadienoic acids

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Aya Umeno ◽  
Mami Sakashita ◽  
Sakiko Sugino ◽  
Kazutoshi Murotomi ◽  
Tsugumi Okuzawa ◽  
...  
Keyword(s):  
Early Stage ◽  
Biological Activities ◽  
Docking Simulation ◽  
Luciferase Reporter ◽  
Water Ligand ◽  
Peroxisome Proliferator ◽  
Agonist Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Abstract Hydroxyoctadecadienoic acids (HODEs) are produced by oxidation and reduction of linoleates. There are several regio- and stereo-isomers of HODE, and their concentrations in vivo are higher than those of other lipids. Although conformational isomers may have different biological activities, comparative analysis of intracellular function of HODE isomers has not yet been performed. We evaluated the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ), a therapeutic target for diabetes, and analyzed PPARγ agonist activity of HODE isomers. The lowest scores for docking poses of 12 types of HODE isomers (9-, 10-, 12-, and 13-HODEs) were almost similar in docking simulation of HODEs into PPARγ ligand-binding domain (LBD). Direct binding of HODE isomers to PPARγ LBD was determined by water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR experiments. In contrast, there were differences in PPARγ agonist activities among 9- and 13-HODE stereo-isomers and 12- and 13-HODE enantio-isomers in a dual-luciferase reporter assay. Interestingly, the activity of 9-HODEs was less than that of other regio-isomers, and 9-(E,E)-HODE tended to decrease PPARγ-target gene expression during the maturation of 3T3-L1 cells. In addition, 10- and 12-(Z,E)-HODEs, which we previously proposed as biomarkers for early-stage diabetes, exerted PPARγ agonist activity. These results indicate that all HODE isomers have PPARγ-binding affinity; however, they have different PPARγ agonist activity. Our findings may help to understand the biological function of lipid peroxidation products.

scholarly journals PPARγ Regulates Triclosan Induced Placental Dysfunction

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 86
Author(s):  
Jing Li ◽  
Xiaojie Quan ◽  
Yue Zhang ◽  
Ting Yu ◽  
Saifei Lei ◽  
...  
Keyword(s):  
Cell Viability ◽  
Opposite Effect ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Placental Dysfunction ◽  
Promising Strategy ◽  
Pparγ Agonist ◽  
Tnf Α

Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus.

scholarly journals PPARγ agonist rosiglitazone prevents perinatal nicotine exposure-induced asthma in rat offspring

2011 ◽  
Vol 300 (5) ◽  
pp. L710-L717 ◽  
Author(s):  
Jie Liu ◽  
Reiko Sakurai ◽  
E. M. O'Roark ◽  
Nicholas J. Kenyon ◽  
John S. Torday ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Peroxisome Proliferator ◽  
Nicotine Exposure ◽  
Concomitant Treatment ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chronic Lung Diseases ◽  
Distal Airway ◽  
Pparγ Agonist

Perinatal exposure to maternal smoke is associated with adverse pulmonary effects, including reduced lung function and increased incidence of asthma. However, the mechanisms underlying these effects are unknown, and there is no effective preventive and/or therapeutic intervention. Recently, we suggested that downregulation of homeostatic mesenchymal peroxisome proliferator-activated receptor-γ (PPARγ) signaling following in utero nicotine exposure might contribute to chronic lung diseases such as asthma. We used an in vivo rat model to determine the effect of perinatal nicotine exposure on 1) offspring pulmonary function, 2) mesenchymal markers of airway contractility in trachea and lung tissue, and 3) whether administration of a PPARγ agonist, rosiglitazone (RGZ), blocks the molecular and functional effects of perinatal nicotine exposure on offspring lung. Pregnant Sprague-Dawley rat dams received placebo, nicotine, or nicotine + RGZ daily from embryonic day 6 until postnatal day 21, when respiratory system resistance, compliance, tracheal contractility, and the expression of markers of pulmonary contractility were determined. A significant increase in resistance and a decrease in compliance under basal conditions, with more pronounced changes following methacholine challenge, were observed with perinatal nicotine exposure compared with control. Tracheal constriction response and expression of mesenchymal markers of airway contractility were also significantly increased following perinatal nicotine exposure. Concomitant treatment with RGZ completely blocked the nicotine-induced alterations in pulmonary function, as well as the markers of airway contractility, at proximal and distal airway levels. These data suggest that perinatal smoke exposure-induced asthma can be effectively blocked by PPARγ agonists.

scholarly journals De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination

2018 ◽  
Vol 217 (4) ◽  
pp. 1353-1368 ◽  
Author(s):  
Laura Montani ◽  
Jorge A. Pereira ◽  
Camilla Norrmén ◽  
Hartmut B.F. Pohl ◽  
Elisa Tinelli ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Ex Vivo ◽  
Intrinsic Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endogenous Fatty Acid ◽  
Pparγ Agonist

Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ–regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator.

scholarly journals SUMO-1 Regulates Body Weight and Adipogenesis via PPARγ in Male and Female Mice

Endocrinology ◽  
2012 ◽  
Vol 154 (2) ◽  
pp. 698-708 ◽  
Author(s):  
Laura Mikkonen ◽  
Johanna Hirvonen ◽  
Olli A. Jänne
Keyword(s):  
Adipose Tissue ◽  
Transcriptional Activation ◽  
Cell Biology ◽  
Target Genes ◽  
The Body ◽  
Peroxisome Proliferator ◽  
Fat Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Properly functioning adipose tissue is essential for normal insulin sensitivity of the body. When mice are kept on high-fat diet (HFD), adipose tissue expands, adipocytes increase in size and number, and the mice become obese. Many of these changes are mediated by the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), the activity of which is regulated by multiple posttranslational modifications, including SUMOylation. To address the role of small ubiquitin-like modifier-1 (SUMO-1) in PPARγ function in vivo, particularly in fat cell biology, we subjected Sumo1-knockout mice to HFD. Sumo1-null mice gained less weight and had smaller and fewer adipocytes in their gonadal fat tissue on HFD, but their glucose tolerance was similar to that of wild-type littermates. Adipogenesis was impaired in Sumo1-null cells, and expression of PPARγ target genes was attenuated. In addition, both Sumo1-null cells and Sumo1-null mice responded less efficiently to rosiglitazone, a PPARγ agonist. These findings indicate that SUMO-1 is important also for transcriptional activation by the PPARγ signaling pathway and not only for trans-repressive functions of PPARγ as previously reported.

scholarly journals Retinoid X Receptor Activation During Adipogenesis of Female Mesenchymal Stem Cells Programs a Dysfunctional Adipocyte

Endocrinology ◽  
2018 ◽  
Vol 159 (8) ◽  
pp. 2863-2883 ◽  
Author(s):  
Bassem M Shoucri ◽  
Victor T Hung ◽  
Raquel Chamorro-García ◽  
Toshi Shioda ◽  
Bruce Blumberg
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Receptor Activation ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Obesity And Diabetes ◽  
Pparγ Agonist

Abstract Early life exposure to endocrine-disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator–activated receptor (PPAR) γ and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ vs RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators (“rexinoids,” 4204 and TBT) attenuate glucose uptake, blunt expression of the antidiabetic hormone adiponectin, and fail to downregulate proinflammatory and profibrotic transcripts, as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.

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