scholarly journals Altered Promoter Recycling Rates Contribute to Dominant-Negative Activity of Human Peroxisome Proliferator-Activated Receptor-γ Mutations Associated with Diabetes

2007 ◽  
Vol 21 (4) ◽  
pp. 857-864 ◽  
Author(s):  
Gang Li ◽  
Todd Leff
Keyword(s):  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Activity

scholarly journals A Novel Peroxisome Proliferator-activated Receptor γ Isoform with Dominant Negative Activity Generated by Alternative Splicing

2005 ◽  
Vol 280 (28) ◽  
pp. 26517-26525 ◽  
Author(s):  
Lina Sabatino ◽  
Amelia Casamassimi ◽  
Gianfranco Peluso ◽  
Maria Vittoria Barone ◽  
Daniela Capaccio ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Activity

Resistance to thyroid hormone, and peroxisome-proliferator-activated receptor γ resistance

2001 ◽  
Vol 29 (2) ◽  
pp. 227-230 ◽  
Author(s):  
V. K. K. Chatterjee
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Thyroid Hormone ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Hormone Binding ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Activity ◽  
Mutant Receptors

Resistance to thyroid hormone (RTH) is usually inherited in a dominant fashion, and is characterized by elevated serum thyroid hormone levels and failure to suppress pituitary secretion of thyroid-stimulating hormone, with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features suggesting predominant pituitary resistance (PRTH). In over 100 families with GRTH or PRTH, we have identified heterozygous mutations in the thyroid hormone receptor β isoform (TRβ), which localize to three regions (amino acids 234–282, 310–353 and 429–461) of the hormone-binding domain of the receptor. The mutant receptors are transcriptionally impaired, due either to reduced ligand binding or to attenuated interaction with co-activators, and inhibit wild-type TR action in a dominant-negative manner. In the TRβ crystal structure, most RTH mutations cluster around the hormone-binding pocket, with receptor regions that mediate functions (DNA binding, dimerization, corepressor recruitment) required for dominant-negative activity being devoid of natural mutations. The pathogenesis of variable tissue resistance is not fully understood, but may be related to the differing tissue distributions of TRα and TRβ, and to variable dominant-negative activity of mutant receptors on different target genes. The nuclear receptor peroxisome-proliferator-activated receptor γ (PPARγ) regulates adipogenesis and mediates the action of thiazolidinediones - novel antidiabetic agents which enhance tissue insulin sensitivity. The PPARγ gene was screened in 85 subjects with severe insulin resistance, and two different heterozygous receptor mutations (P467L and V290M) were identified in three affected individuals. The PPARγ mutants are markedly transcriptionally impaired due to altered ligand binding and co-activator recruitment. Analogous to RTH, they inhibit the function of wild-type PPARγ when co-expressed, and such dominant-negative inhibition is linked to their ability to silence basal gene transcription via aberrant interaction with co-repressors. In addition to insulin resistance, all three affected subjects developed Type II diabetes mellitus and hypertension at an unusually early age. Our findings provide compelling evidence that PPARγ is important in the control of insulin sensitivity, glucose homoeostasis and blood pressure in humans. Future studies aim to elucidate the mechanism by which this receptor regulates insulin action and vascular tone.

scholarly journals A Truncated Human Peroxisome Proliferator-Activated Receptor α Splice Variant with Dominant Negative Activity

1999 ◽  
Vol 13 (9) ◽  
pp. 1535-1549 ◽  
Author(s):  
Philippe Gervois ◽  
Inés Pineda Torra ◽  
Giulia Chinetti ◽  
Thilo Grötzinger ◽  
Guillaume Dubois ◽  
...  
Keyword(s):  
Splice Variant ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Activity

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3271-3280 ◽  
Author(s):  
Istvan Szatmari ◽  
Daniel Töröcsik ◽  
Maura Agostini ◽  
Tibor Nagy ◽  
Mark Gurnell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lipid Metabolism ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Positive Effects ◽  
Dominant Negative Mutation ◽  
Human Dendritic Cells

Abstract Activation of the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) modifies the immunophenotype of monocyte-derived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.

scholarly journals CREB Activation Induces Adipogenesis in 3T3-L1 Cells

2000 ◽  
Vol 20 (3) ◽  
pp. 1008-1020 ◽  
Author(s):  
Jane E. B. Reusch ◽  
Lilliester A. Colton ◽  
Dwight J. Klemm
Keyword(s):  
Transcription Factor ◽  
Dominant Negative ◽  
Marker Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Fat Composition ◽  
Specific Factors ◽  
Necessary And Sufficient ◽  
Physiological And Biochemical

ABSTRACT Obesity is the result of numerous, interacting behavioral, physiological, and biochemical factors. One increasingly important factor is the generation of additional fat cells, or adipocytes, in response to excess feeding and/or large increases in body fat composition. The generation of new adipocytes is controlled by several “adipocyte-specific” transcription factors that regulate preadipocyte proliferation and adipogenesis. Generally these adipocyte-specific factors are expressed only following the induction of adipogenesis. The transcription factor(s) that are involved in initiating adipocyte differentiation have not been identified. Here we demonstrate that the transcription factor, CREB, is constitutively expressed in preadipocytes and throughout the differentiation process and that CREB is stimulated by conventional differentiation-inducing agents such as insulin, dexamethasone, and dibutyryl cAMP. Stably transfected 3T3-L1 preadipocytes were generated in which we could induce the expression of either a constitutively active CREB (VP16-CREB) or a dominant-negative CREB (KCREB). Inducible expression of VP16-CREB alone was sufficient to initiate adipogenesis as determined by triacylglycerol storage, cell morphology, and the expression of two adipocyte marker genes, peroxisome proliferator activated receptor gamma 2, and fatty acid binding protein. Alternatively, KCREB alone blocked adipogenesis in cells treated with conventional differentiation-inducing agents. These data indicate that activation of CREB was necessary and sufficient to induce adipogenesis. Finally, CREB was shown to bind to putative CRE sequences in the promoters of several adipocyte-specific genes. These data firmly establish CREB as a primary regulator of adipogenesis and suggest that CREB may play similar roles in other cells and tissues.

scholarly journals LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues

2014 ◽  
Vol 53 (1) ◽  
pp. 117-130 ◽  
Author(s):  
Amélie Gormand ◽  
Christine Berggreen ◽  
Lahouari Amar ◽  
Emma Henriksson ◽  
Ingrid Lund ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Histone Deacetylases ◽  
Fatty Acid Synthase ◽  
Nuclear Translocation ◽  
Adipogenic Differentiation ◽  
Camp Response Element Binding ◽  
Dominant Negative ◽  
Hormone Sensitive Lipase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

cAMP-response element-binding protein (CREB) is required for the induction of adipogenic transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs). Interestingly, it is known from studies in other tissues that LKB1 and its substrates AMP-activated protein kinase (AMPK) and salt-inducible kinases (SIKs) negatively regulate gene expression by phosphorylating the CREB co-activator CRTC2 and class IIa histone deacetylases (HDACs), which results in their exclusion from the nucleus where they co-activate or inhibit their targets. In this study, we show that AMPK/SIK signalling is acutely attenuated during adipogenic differentiation of 3T3-L1 preadipocytes, which coincides with the dephosphorylation and nuclear translocation of CRTC2 and HDAC4. When subjected to differentiation, 3T3-L1 preadipocytes in which the expression of LKB1 was stably reduced using shRNA (Lkb1-shRNA), as well as Lkb1-knockout mouse embryonic fibroblasts (Lkb1−/− MEFs), differentiated more readily into adipocyte-like cells and accumulated more triglycerides compared with scrambled-shRNA-expressing 3T3-L1 cells or Wt MEFs. In addition, the phosphorylation of CRTC2 and HDAC4 was reduced, and the mRNA expression of adipogenic transcription factors Cebpa, peroxisome proliferator-activated receptor γ (Pparg) and adipocyte-specific proteins such as hormone-sensitive lipase (HSL), fatty acid synthase (FAS), aP2, GLUT4 and adiponectin was increased in the absence of LKB1. The mRNA and protein expression of Ddit3/CHOP10, a dominant-negative member of the C/EBP family, was reduced in Lkb1-shRNA-expressing cells, providing a potential mechanism for the up-regulation of Pparg and Cebpa expression. These results support the hypothesis that LKB1 signalling keeps preadipocytes in their non-differentiated form.

scholarly journals Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-α(PPARα)

PPAR Research ◽  
2006 ◽  
Vol 2006 ◽  
pp. 1-9 ◽  
Author(s):  
Eric S. Tien ◽  
Daniel B. Hannon ◽  
Jerry T. Thompson ◽  
John P. Vanden Heuvel
Keyword(s):  
Conformational Change ◽  
Peptide Library ◽  
Dominant Negative ◽  
Carboxyl Terminus ◽  
Peroxisome Proliferator ◽  
Agonist Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Steroid Receptor Coactivator ◽  
Important Protein ◽  
Receptor Modulators

The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-α(PPARα) was examined. PPAR-binding protein (PBP), PPARγcoactivator-1α(PGC-1α), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPARαactivity in the presence of Wy-14,643. The effects on PPARαactivity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1α, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1α. The interaction of PPARαwith an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPARαoccurs predominantly via the carboxyl-terminus and mutating456LHPLL to456LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPARαis ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely.

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