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Peroxisome proliferator-activated receptor gamma controls Muc1 transcription in trophoblasts
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Shalom-Barak T Nicholas JM Wang Y Zhang X Ong ES Young TH Gendler SJ Evans RM Barak Y 《Molecular and cellular biology》2004,24(24):10661-10669
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for placental development. Here, we show that the mucin gene Muc1 is a PPARgamma target, whose expression is lost in PPARgamma null placentas. During differentiation of trophoblast stem cells, PPARgamma is strongly induced, and Muc1 expression is upregulated by the PPARgamma agonist rosiglitazone. Muc1 promoter is activated strongly and specifically by liganded PPARgamma but not PPARalpha or PPARdelta. A PPAR binding site (DR1) in the proximal Muc1 promoter acts as a basal silencer in the absence of PPARgamma, and its cooperation with a composite upstream enhancer element is both necessary and sufficient for PPARgamma-dependent induction of Muc1. In the placenta, MUC1 protein is localized exclusively to the apical surface of the labyrinthine trophoblast around maternal blood sinuses, resembling its luminal localization on secretory epithelia. Last, variably penetrant maternal blood sinus dilation in Muc1-deficient placentas suggests that Muc1 regulation by PPARgamma contributes to normal placental development but also that the essential functions of PPARgamma in the organ are mediated by other targets. 相似文献
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Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells 总被引:6,自引:0,他引:6
Faveeuw C Fougeray S Angeli V Fontaine J Chinetti G Gosset P Delerive P Maliszewski C Capron M Staels B Moser M Trottein F 《FEBS letters》2000,486(3):261-266
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. They are divided into three subtypes (alpha, beta or delta, and gamma) and are involved in lipid and glucose homeostasis and in the control of inflammation. In this study, we analyzed the expression of PPARs in murine dendritic cells (DCs), the most potent antigen presenting cells. We find that immature as well as mature spleen-derived DCs express PPARgamma, but not PPARalpha, mRNA and protein. We also show that the PPARgamma activator rosiglitazone does not interfere with the maturation of DCs in vitro nor modifies their ability to activate naive T lymphocytes in vivo. Finally, we present evidence that PPARgamma activators down-modulate the CD40-induced secretion of interleukin-12, a potent Th1-driving factor. These data suggest a possible role for PPARgamma in the regulation of immune responses. 相似文献
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Peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the differentiation of intestinal cells and tissues. Our previous reports indicate that PPARγ is expressed at considerable levels in human colon cancer cells. This suggests that PPARγ expression may be an important factor for cell growth regulation in colon cancer. In this study, we investigated PPARγ expression in 4 human colon cancer cell lines, HT-29, LOVO, DLD-1, and Caco-2. Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that the relative levels of PPARγ mRNA and protein in these cells were in the order HT-29>LOVO>Caco-2>DLD-1. We also found that PPARγ overexpression promoted cell growth inhibition in PPARγ lower-expressing cell lines (Caco-2 and DLD-1), but not in higher-expressing cells (HT-29 and LOVO). We observed a correlation between the level of PPARγ expression and the cells' sensitivity for proliferation. 相似文献
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Pakala R Kuchulakanti P Rha SW Cheneau E Baffour R Waksman R 《Cardiovascular radiation medicine》2004,5(2):97-103
Here we review PPARgamma function in relation to human adipogenesis, insulin sensitization, lipid metabolism, blood pressure regulation and prothrombotic state to perhaps provide justification for this nuclear receptor remaining a key therapeutic target for the continuing development of agents to treat human metabolic syndrome. 相似文献
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Gupta RA Sarraf P Brockman JA Shappell SB Raftery LA Willson TM DuBois RN 《The Journal of biological chemistry》2003,278(9):7431-7438
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Chen L Necela BM Su W Yanagisawa M Anastasiadis PZ Fields AP Thompson EA 《The Journal of biological chemistry》2006,281(34):24575-24587
Peroxisome proliferator-activated receptor gamma (PPARgamma) causes epithelial to mesenchymal transformation (EMT) in intestinal epithelial cells, as evidenced by reorganization of the actin cytoskeleton, acquisition of a polarized, mesenchymal cellular morphology, increased cellular motility, and colony scattering. This response is due to activation of Cdc42, resulting in p21-activated kinase-dependent phosphorylation and activation of MEK1 Ser(298) and activation of ERK1/2. Dominant negative MEK1, MEK2, and ERK2 block PPARgamma-induced EMT, whereas constitutively active MEK1 and MEK2 induce a mesenchymal phenotype similar to that evoked by PPARgamma. PPARgamma also stimulates ERK1/2 phosphorylation in the intestinal epithelium in vivo. PPARgamma induces the p110alpha subunit of phosphoinositide 3-kinase (PI3K), and inhibition of PI3K blocks PPARgamma-dependent phosphorylation of MEK1 Ser(298), activation of ERK1/2, and EMT. We conclude that PPARgamma regulates the motility of intestinal epithelial cells through a mitogen-activated protein kinase cascade that involves PI3K, Cdc42, p21-activated kinase, MEK1, and ERK1/2. Regulation of cellular motility through Rho family GTPases has not been previously reported for nuclear receptors, and elucidation of the mechanism that accounts for the role of PPARgamma in regulating motility of intestinal epithelial cells provides fundamental new insight into the function of this receptor during renewal of the intestinal epithelium. 相似文献
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Peroxisome proliferator-activated receptor gamma induces pancreatic cancer cell apoptosis 总被引:4,自引:0,他引:4
Eibl G Wente MN Reber HA Hines OJ 《Biochemical and biophysical research communications》2001,287(2):522-529
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) decreases the growth of certain cancer cells. In the present study, we found that six different human pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, HPAF-II, MIA PaCa-2, and PANC-1) expressed PPAR-gamma m-RNA and synthesized the protein. The endogenous and exogenous PPAR-gamma ligands 15-deoxy-d12,14-prostaglandin J(2) (15-PGJ(2)) and ciglitazone decreased cell number, cell viability, and increased floating/attached ratio, in a time- and dose-dependent fashion. 15-PGJ(2) increased intracellular nucleosome concentration after 6 h, but did not increase caspase-3 activity even after 96 h. Combined treatment with both 15-PGJ(2) and the caspase-3 inhibitor DEVD-CHO had no effect on cell viability, but the general caspase inhibitor ZVAD-FMK reduced 15-PGJ(2)-induced apoptosis. We concluded that the six human pancreatic cancer cells tested all expressed PPAR-gamma receptor, and treatment with PPAR-gamma agonists decreased cell viability and growth in a time- and dose-dependent manner. These effects were partially mediated by induction of caspase-3 independent apoptosis. 相似文献
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Castriota G Thompson GM Lin Y Scherer PE Moller DE Berger JP 《Cell biology international》2007,31(6):586-591
alpha1-Acid glycoprotein (alpha1-AGP) is an acute phase protein that can potentiate cytokine secretion by mononuclear cells and may induce thrombosis by stabilizing the inhibitory activity of plasminogen activator inhibitor-1. Thus, alpha1-AGP may promote pathobiologies associated with type 2 diabetes mellitus (T2DM) including insulin resistance and cardiovascular disease. Here, we demonstrate that antidiabetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists inhibited expression of 3T3-L1 adipocyte alpha1-AGP in a concentration- and time-dependent manner via an apparent PPARgamma-mediated mechanism. As a result, synthesis and secretion of the glycoprotein was reduced. While PPARgamma agonist regulation of genes with functional peroxisome proliferator response elements in their promoter such as phosphoenolpyruvate carboxykinase were unaffected when cellular protein synthesis was inhibited, downregulation of alpha1-AGP mRNA was ablated thereby supporting the proposition that PPARgamma activation inhibits alpha1-AGP expression indirectly. These results suggest a potential novel adipocytic mechanism by which PPARgamma agonists may ameliorate T2DM-associated insulin resistance and cardiovascular disease. 相似文献
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Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells 总被引:2,自引:0,他引:2
Jaster R Lichte P Fitzner B Brock P Glass A Karopka T Gierl L Koczan D Thiesen HJ Sparmann G Emmrich J Liebe S 《Journal of cellular and molecular medicine》2005,9(3):670-682
Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro-fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARgamma ligands, however, are at least in part mediated through PPARgamma-independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARgamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPARgamma overexpression. Induction of PPARgamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARgamma-overexpressing cells synthesised less collagen than controls. To monitor effects of PPARgamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up- and 19 down-regulated genes in PPARgamma-overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentiation. In conclusion, our data suggest an active role of PPARgamma in the induction of a quiescent PSC phenotype. PPARgamma-regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies. 相似文献
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Pakala R Rha SW Kuchulakanti PK Cheneau E Baffour R Waksman R 《Cardiovascular radiation medicine》2004,5(1):44-48
Cellular proliferation and migration are fundamental processes that contribute to the injury response in major blood vessels. The resultant pathologies are atherosclerosis and restenosis. As we begin to understand the cellular changes associated with vascular injury, it is critical to determine whether the inhibition of growth and movement of cells in the vasculature could serve as a novel therapeutic strategy to prevent atherosclerosis and restenosis. 相似文献
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Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates trefoil factor family 2 (TFF2) expression in gastric epithelial cells 总被引:1,自引:0,他引:1
Shimada T Fujii Y Koike T Tabei K Namatame T Yamagata M Tajima A Yoneda M Terano A Hiraishi H 《The international journal of biochemistry & cell biology》2007,39(3):626-637
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M T Leininger C P Portocarrero K L Houseknecht 《Biochemical and biophysical research communications》1999,263(3):749-753
Peroxisome proliferator-activated receptor gamma (PPARgamma), a primary regulator of adipocyte differentiation, has been implicated in the regulation of monocyte and macrophage function in vitro. We report that PPARgamma protein is expressed in porcine peripheral white blood cells (WBC), and that PPARgamma1 but not gamma2 mRNA predominates. Additionally, we provide the first evidence that in vivo lipopolysaccharide challenge (LPS, 25 microg/kg BW) causes a dynamic increase in PPARgamma protein expression in peripheral WBC (P < 0.05). PPARgamma expression was increased 2-fold over basal (1 hr post-LPS), was maximal by 4 hr (3-fold), and was normalized to control by 8 hr post-LPS. Changes in PPARgamma expression coincided with or closely followed LPS-induced changes in plasma cortisol, TNF-alpha, insulin, IGF-1, glucose, and free fatty acids. These data suggest that induction of PPARgamma expression in WBC may play a role in host response to acute inflammatory challenge and may prove to be an important target of anti-inflammatory therapies. 相似文献
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Peroxisome proliferator-activated receptor gamma inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells 总被引:5,自引:0,他引:5
Bruemmer D Yin F Liu J Berger JP Kiyono T Chen J Fleck E Van Herle AJ Forman BM Law RE 《Molecular endocrinology (Baltimore, Md.)》2003,17(6):1005-1018
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