Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous investigations have evidenced the importance of CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor (PPAR)gamma for lung development, especially for alveolar type II cells (ATII). This prompted us to explore whether ATII maturation-promoting mediators controlled their expression in isolated ATII. In whole rat lung, C/EBPalpha, beta, delta, and PPARgamma mRNAs increased 3-5 times between gestational day 18 and term (Day 22), dropped around birth, then reincreased. C/EBPbeta and delta, but not PPARgamma, displayed similar profile in isolated ATII; C/EBPalpha transcript disappeared and the protein became hardly detectable in isolated cells. In cultured ATII, dexamethasone increased C/EBPbeta and PPARgamma mRNAs 2-4 times, and cyclic AMP increased C/EBPbeta and delta mRNAs approximately 1.5 times. Whereas retinoic acid increased C/EBPbeta and PPARgamma mRNAs 1.5 times in ATII in vitro, vitamin-A deficiency strongly decreased fetal lung C/EBPalpha, beta, and PPARgamma transcripts in vivo. C/EBPbeta, delta, and PPARgamma mRNAs were also increased in vitro by epidermal growth factor and keratinocyte growth factor, whereas they were unchanged by the maturation inhibitor transforming growth factor-beta. C/EBPalpha expression was not reinduced by any mediator. Changes in transcripts were reflected in protein levels analyzed through Western blotting. These results argue for a role of these factors in ATII functional maturation, and indicate a multifactorial control of their ontogeny.
Am J Respir Cell Mol Biol 2003 Nov
PMID:Maturational factors modulate transcription factors CCAAT/enhancer-binding proteins alpha, beta, delta, and peroxisome proliferator-activated receptor-gamma in fetal rat lung epithelial cells. 1456 82

Matrix metalloproteinases (MMPs) degrade extracellular matrix components, and overexpression of these enzymes contributes to tissue destruction in arthritis. Of particular importance are the collagenases, MMP-1 and MMP-13, which have high activity against the interstitial collagens in cartilage. In this study, we address the mechanisms of two inhibitors of collagenase gene expression, the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta(12,14)-prostaglandin J2 (15-dPGJ2). Although both inhibitors are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a connection between PPAR-gamma and collagenase gene expression has yet to be established. Here, we test the hypothesis that CDDO and 15-dPGJ2 use PPAR-gamma to repress MMP gene expression. Our findings with the PPAR-gamma antagonist 2-[4-[2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl]rsqb]-phenylsulfanyl]-2-methylpropionic acid (GW9662) and mouse embryonic fibroblasts lacking PPAR-gamma demonstrate that CDDO and 15-dPGJ2 use PPAR-gamma-independent mechanisms to inhibit collagenase gene expression. To address a potential PPAR-gamma-independent mechanism leading to the repression of MMPs by CDDO, we tested the effect of CDDO on the transforming growth factor-beta (TGF-beta) signaling pathway. We found that CDDO requires Smads (transcription factors activated by TGF-beta) for the repression of MMP-1. Specifically, MMP-1 is inhibited neither by CDDO in the absence of TGF-beta receptor-activated Smad3 nor when a negative regulator, Smad7, attenuates TGF-beta signaling. We conclude that CDDO represses MMP gene expression through a novel PPAR-gamma-independent mechanism that requires Smad signaling.
Mol Pharmacol 2004 Feb
PMID:Peroxisome proliferator-activated receptor-gamma-independent repression of collagenase gene expression by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and prostaglandin 15-deoxy-delta(12,14) J2: a role for Smad signaling. 1474 72

Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor lacking identified natural ligands. We have addressed the requirements for ERRgamma-mediated gene regulation. ERRgamma transactivates constitutively reporter genes driven by ERR response elements (ERREs) or estrogen response elements (EREs). The activation depends on an intact DNA-binding domain (DBD) and activation function-2 (AF2). ERRgamma-mediated transactivation is further enhanced by peroxisome proliferator-activated receptor coactivator-1. Interestingly, ligand-binding domain (LBD) mutations predicted to either enlarge or diminish the putative ligand-binding pocket have no effect on the transcriptional activity implying that ERRgamma activity does not depend on any ligands. Antiestrogens 4OH-tamoxifen (4OHT) and 4-hydroxytoremifene (4OHtor) inhibit the ability of ERR to transactivate ERRE and ERE reporters. In contrast, ERRgamma activates transcription at AP-1 sites in the presence of 4OHT and 4OHtor. Thus, the transcriptional activity of ERRgamma seems not to require ligand binding but is modulated by binding of certain small synthetic ligands.
Mol Cell Endocrinol 2004 Apr 30
PMID:Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma. 1514 36

The cyclopentenone prostaglandin and PPARgamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) displays anti-inflammatory effects in several experimental models. Direct modification of protein thiols is arising as an important mechanism of cyclopentenone prostaglandin action. However, little is known about the extent or specificity of this process. Mesangial cells (MC) play a key role in glomerulonephritis. In this work, we have studied the selectivity of protein modification by 15d-PGJ(2) in MC, and the correlation with the modulation of several proinflammatory genes. MC incubation with biotinylated 15d-PGJ(2) results in the labeling of a distinct set of proteins as evidenced by two-dimensional electrophoresis. 15d-PGJ(2) binds to nuclear and cytosolic targets as detected by fluorescence microscopy and subcellular fractionation. The pattern of biotinylated 15d-PGJ(2)-modified polypeptides is readily distinguishable from that of total protein staining or labeling with biotinylated iodoacetamide. 15d-PGJ(2) addition requires the double bond in the cyclopentane ring. 9,10-Dihydro-15d-PGJ(2), a 15d-PGJ(2) analog that shows the same potency as peroxisome proliferator-activated receptor (PPAR) agonist in MC but lacks the cyclopentenone moiety, displays reduced ability to modify proteins and to block 15d-PGJ(2) binding. Micromolar concentrations of 15d-PGJ(2) inhibit cytokine-elicited levels of inducible nitricoxide synthase, cyclooxygenase-2, and intercellular adhesion molecule-1 in MC. In contrast, 9,10-dihydro-15d-PGJ(2) does not reproduce this inhibition. 15d-PGJ(2) effect is not blocked by the PPARgamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Moreover, compounds possessing an alpha,beta-unsaturated carbonyl group, like 2-cyclopenten-1-one and 2-cyclohexen-1-one, reduce pro-inflammatory gene expression. These observations indicate that covalent modification of cellular thiols by 15d-PGJ(2) is a selective process that plays an important role in the inhibition of MC responses to pro-inflammatory stimuli.
Mol Pharmacol 2004 Nov
PMID:Protein thiol modification by 15-deoxy-Delta12,14-prostaglandin J2 addition in mesangial cells: role in the inhibition of pro-inflammatory genes. 1531 73

Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine, reduces pain and inflammation through an as-yet-uncharacterized mechanism. Here, we identify the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) as the molecular target responsible for the anti-inflammatory properties of PEA. PEA selectively activates PPAR-alpha in vitro with an EC(50) value of 3.1 +/- 0.4 microM and induces the expression of PPAR-alpha mRNA when applied topically to mouse skin. In two animal models, carrageenan-induced paw edema and phorbol ester-induced ear edema, PEA attenuates inflammation in wild-type mice but has no effect in mice deficient in PPAR-alpha. The natural PPAR-alpha agonist oleoylethanolamide (OEA) and the synthetic PPAR-alpha agonists GW7647 and Wy-14643 mimic these effects in a PPAR-alpha-dependent manner. These findings indicate that PPAR-alpha mediates the anti-inflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPAR-alpha.
Mol Pharmacol 2005 Jan
PMID:The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. 1546 22

Human aldo-keto reductases (AKRs) regulate nuclear receptors by controlling ligand availability. Enzymes implicated in regulating ligand occupancy and trans-activation of the nuclear receptors belong to the AKR1C family (AKR1C1-AKR1C3). Nuclear receptors regulated by AKR1C members include the steroid hormone receptors (androgen, estrogen, and progesterone receptors) and the orphan peroxisome proliferator-activated receptor (PPARgamma). In human myeloid leukemia (HL-60) cells, ligand access to PPARgamma is regulated by AKR1C3, which diverts PGD(2) metabolism away from J-series prostanoids (Desmond et al., 2003). Inhibition of AKR1C3 by indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), caused PPARgamma-mediated terminal differentiation of the HL-60 cells. To discriminate between antineoplastic effects of NSAIDs that are mediated by either AKR1C or cyclooxygenase (COX) isozymes, selective inhibitors are required. We report a structural series of N-phenylanthranilic acid derivatives and steroid carboxylates that selectively inhibit recombinant AKR1C isoforms but do not inhibit recombinant COX-1 or COX-2. The inhibition constants, IC(50), K(I) values, and inhibition patterns were determined for the NSAID analogs and steroid carboxylates against AKR1C and COX isozymes. Lead compounds, 4-chloro-N-phenylanthranilic acid and 4-benzoyl-benzoic acid for the N-phenylanthranilic acid analogs and most steroid carboxylates, exhibited IC(50) values that had greater than 500-fold selectivity for AKR1C isozymes compared with COX-1 and COX-2. Crystallographic and molecular modeling studies showed that the carboxylic acid of the inhibitor ligand was tethered by the catalytic Tyr55-OH(2)(+) and explained why A-ring substituted N-phenylanthranilates inhibited only AKR1C enzymes. These compounds can be used to dissect the role of the AKR1C isozymes in neoplastic diseases and may have cancer chemopreventive roles independent of COX inhibition.
Mol Pharmacol 2005 Jan
PMID:Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms: potential antineoplastic agents that work independently of cyclooxygenase isozymes. 1547 69

Ertiprotafib belongs to a novel class of insulin sensitizers developed for treatment of type 2 diabetes. In insulin-resistant rodent models, ertiprotafib and a close analog lowered both fasting blood glucose and insulin levels and improved glycemic excursion during an oral glucose tolerance test. In addition, treatment of rodents improved lipid profiles, with significantly lowered triglyceride and free fatty acid levels. These results suggested that this therapeutic activity might involve mechanisms in addition to PTP1b inhibition. In this study, we demonstrate that ertiprotafib activates peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma at concentrations comparable with those of known agonists of these regulators. Furthermore, it is able to drive adipocyte differentiation of C3H10T(1/2) cells, a hallmark of PPARgamma activation. Livers from ertiprotafib-treated animals showed significant induction of acyl-CoA oxidase activity, probably caused by PPARalpha engagement in these animals. We also show that ertiprotafib inhibits PTP1b in vitro with nonclassic kinetics at concentrations above its EC(50) for PPAR agonism. Thus, the complete mechanism of action for ertiprotafib and related compounds in vivo may involve multiple independent mechanisms, including (but not necessarily limited to) PTP1b inhibition and dual PPARalpha/PPARgamma agonism. Ertiprotafib pharmacology and interpretation of clinical results must be seen in light of this complexity.
Mol Pharmacol 2005 Jan
PMID:Ertiprotafib improves glycemic control and lowers lipids via multiple mechanisms. 1547 71

Fatty acids are an important ligand for peroxisome proliferator-activated receptor (PPAR) activation and transcriptional regulation of metabolic genes. To examine whether reduced plasma free fatty acid (FFA) availability affects the mRNA content of proteins involved in fuel metabolism in vivo, the skeletal muscle mRNA content of various transcription factors, transcriptional coactivators and genes encoding for lipid regulatory proteins were examined before and after 3 h of cycle exercise with (NA) and without (CON) pre-exercise ingestion of nicotinic acid (NA). NA resulted in a marked (3- to 6-fold) increase (P<0.05) in PPARalpha, PPARdelta and PPAR coactivator 1alpha (PGC1alpha) mRNA, but was without effect on nuclear respiratory factor-1 and Forkhead transcription factor, fatty acid transcolase/CD36, carnitine palmitoyl transferase 1, hormone sensitive lipase (HSL) and pyruvate dehydrogenase kinase 4. Exercise in CON was associated with increased (P<0.05) PPARalpha, PPARdelta and PGC1alpha mRNA, which was similar in magnitude to levels observed with NA at rest. Exercise was generally without effect on the mRNA content of lipid regulatory proteins in CON and did not affect the mRNA content of the measured subset of transcription factors, transcriptional co-activators and lipid regulatory proteins during NA. To determine the possible mechanisms by which NA might affect PGC1alpha expression, we measured p38 MAP kinase (MAPK) and plasma epinephrine. Phosphorylation of p38 MAPK was increased (P<0.05) by NA treatment at rest, and this correlated (r2=0.84, P<0.01) with increased PGC1alpha. Despite this close relationship, increasing p38 MAPK in human primary myotubes was without effect on PGC1alpha mRNA content. Plasma epinephrine was elevated (P<0.05) by NA at rest (CON: 0.27+/-0.06, NA: 0.72+/-0.11 nM) and throughout exercise. Incubating human primary myotubes with epinephrine increased PGC1alpha independently of changes in p38 MAPK phosphorylation. Hence, despite the fact that NA ingestion decreased FFA availability, it promoted the induction of PPARalpha/delta and PGC1alpha gene expression to a similar degree as prolonged exercise. We suggest that the increase in PGC1alpha may be due to the elevated plasma epinephrine levels. Despite these changes in transcription factors/coactivators, the mRNA content of lipid regulatory proteins was generally unaffected by plasma FFA availability.
J Mol Endocrinol 2004 Oct
PMID:Suppression of plasma free fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) alpha and delta and PPAR coactivator 1alpha in human skeletal muscle, but not lipid regulatory genes. 1552 7

Insulin-induced gene-1 (Insig-1) and its homolog Insig-2 encode closely related proteins of the endoplasmic reticulum that block proteolytic activation of sterol regulatory element binding proteins, membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells. These proteins also restrict lipogenesis in mature adipocytes and block differentiation of preadipocytes. Herein, we identified a novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] response element in the promoter region of Insig-2 gene, which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. Interestingly, 1,25-(OH)2D3 is known to directly suppress the expression of peroxisome proliferator-activated receptor gamma2 protein and inhibits adipocyte differentiation of 3T3-L1 preadipocytes and murine bone marrow stromal cells. Consistent with an idea that the antiadipogenic action of 1,25-(OH)2D3 may also involve up-regulation of Insig-2, we found that 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR, and collectively our results suggest an intriguing, new linkage between 1,25-(OH)2D3 and lipogenesis.
Mol Endocrinol 2005 Feb
PMID:Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes. 1552 75

Suppressor of cytokine signaling-2 (SOCS2)-deficient (SOCS2-/-) mice grow significantly larger than their littermates, suggesting that SOCS2 is important in the negative regulation of the actions of GH and/or IGF-I. The aim of this study was to identify genes and metabolic parameters that might contribute to the SOCS2-/- phenotype. We demonstrate that although SOCS2 deficiency induces significant changes in hepatic gene expression, only a fraction of these overlap with known GH-induced effects in the liver, suggesting that SOCS2 might be an important regulator of other growth factors and cytokines acting on the liver. However, an important role of GH and IGF-I in the phenotype of these animals was demonstrated by an overexpression of IGF-binding protein-3 mRNA in the liver and increased levels of circulating IGF-binding protein-3. Other GH-like effects included diminished serum triglycerides and down-regulation of lipoprotein lipase in adipose tissue. Interestingly, SOCS2-/- mice did not differ from their wild-type littermates in glucose or insulin tolerance tests, which is in contrast with the known diabetogenic effects of GH. Furthermore, there was no evidence of impaired insulin signaling in primary hepatocytes isolated from SOCS2-/- mice. Moreover, increased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA was detected in skeletal muscle, which might contribute to normal glycemic control despite the apparent overactivity of the GH/IGF-I axis. Our data indicate that SOCS2 deficiency partially mimics a state of increased GH activity, but also results in changes that cannot be related to known GH effects.
Mol Endocrinol 2005 Mar
PMID:Suppressor of cytokine signaling-2 deficiency induces molecular and metabolic changes that partially overlap with growth hormone-dependent effects. 1556 48


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