Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P31749 (AKT)
22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

15-deoxy-Delta(12,14) prostaglandin J(2) (15dPGJ(2)), a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, induced synergistic stimulation of DNA synthesis in the presence of phorbol dibutyrate (PDB) in Swiss 3T3 cells. This effect was dose-dependent and the maximum response was obtained at 2 microM 15dPGJ(2), although higher concentrations of 15dPGJ(2) were cytotoxic. Furthermore, 15dPGJ(2) synergizes with PDB to induce cell-cycle progression and cyclin D(1) expression. Rosiglitazone and ciglitazone, two other agonists of PPARgamma, did not synergize with PDB to induce DNA synthesis, suggesting that activation of PPARgamma is not involved in 15dPGJ(2)-induced DNA synthesis. 15dPGJ(2) neither increased the levels of cAMP, nor changed the phosphorylation state of CREB, nor induced calcium mobilization, indicating that 15dPGJ(2) effects are independent of prostaglandin D(2) receptor (DP1 and DP2). Moreover, 15dPGJ(2) did not induce activation of PKB/AKT or activation of extracellular signal-regulated kinase (ERK). These results establish a proliferative role for 15dPGJ(2) in Swiss 3T3 cells independent of the activation of PPARgamma or the PGD(2) receptors.
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PMID:15-deoxy-delta12,14 prostaglandin J2 synergizes with phorbol ester to induce proliferation in Swiss 3T3 cells independently of peroxisome proliferator-activated receptor gamma and PGD2 receptors. 1270 51

Interleukin-4 (IL-4) activates STAT6 in 3T3-L1 preadipocytes but its functional role is not known. In this report, we first assessed interleukin-4 receptor alpha (IL-4Ralpha) expression during adipogenesis. IL-4Ralpha was highly expressed in proliferating 3T3-L1 preadipocytes. Receptor expression was down-regulated in post-confluent growth arrested preadipocytes. Induction of differentiation led to a transient 36-h increase in expression, but then levels decreased to undetectable amounts 3-8 days after induction of differentiation. Depending on the cell type, IL-4 either increases or decreases cell proliferation. In growth arrested preconfluent 3T3-L1 preadipocytes, IL-4 alone had no effect on preadipocyte proliferation. In contrast, IL-4 inhibited platelet-derived growth factor (PDGF-BB) induced preadipocyte proliferation. PDGF-BB, but not IL-4, induced STAT3 tyrosine and AKT serine phosphorylation. Both PDGF-BB and IL-4 induced STAT6 tyrosine phosphorylation, but the bands showed distinct electrophoretic migration patterns. IL-4 alone and IL-4 added to the differentiation cocktail had no effect on adipocyte formation or PPARgamma expression. Collectively, these studies demonstrate that IL-4 inhibits PDGF-BB-induced preadipocyte proliferation, possibly through STAT6 activation. The pattern of IL-4 receptor expression suggests that the effects of IL-4 are targeted primarily towards preadipocytes.
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PMID:Interleukin-4 inhibits platelet-derived growth factor-induced preadipocyte proliferation. 1469 61

Here, we demonstrated that inhibition of mTOR with rapamycin has negative effects on adipocyte differentiation and insulin signaling. Rapamycin significantly reduced expression of most adipocyte marker genes including PPARgamma, adipsin, aP2, ADD1/SREBP1c, and FAS, and decreased intracellular lipid accumulation in 3T3-L1 and 3T3-F442A cells, suggesting that rapamycin would affect both lipogenesis and adipogenesis. Contrary to the previous report that suppressive effect of rapamycin on adipogenesis is limited to the clonal expansion, we revealed that its inhibitory effect persisted throughout the process of adipocyte differentiation. Thus, it is likely that constitutive activation of mTOR might be required for the execution of adipogenic programming. In differentiated 3T3-L1 adipocytes, chronic treatment of rapamycin blunted the phosphorylation of AKT and GSK, which is stimulated by insulin, and reduced insulin-dependent glucose uptake activity. Taken together, these results suggest that rapamycin not only prevents adipocyte differentiation by decrease of adipogenesis and lipogenesis but also downregulates insulin action in adipocytes, implying that mTOR would play important roles in adipogenesis and insulin action.
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PMID:Regulation of adipocyte differentiation and insulin action with rapamycin. 1535 18

The signaling pathway of phosphatidylinositol 3-kinase (PI3K)/AKT, which is involved in cell survival, proliferation, and growth, has become a major focus in targeting cancer therapeutics. Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was previously identified as a gene induced by several anti-tumorigenic compounds including nonsteroidal anti-inflammatory drugs, peroxisome proliferator-activated receptor gamma ligands, and dietary compounds. NAG-1 has been shown to exhibit anti-tumorigenic and/or pro-apoptotic activities in vivo and in vitro. In this report, we showed a PI3K/AKT/glycogen synthase kinase-3beta (GSK-3beta) pathway regulates NAG-1 expression in human colorectal cancer cells as assessed by the inhibition of PI3K, AKT, and GSK-3beta. PI3K inhibition by LY294002 showed an increase in NAG-1 protein and mRNA expression, and 1l-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate (AKT inhibitor) also induced NAG-1 expression. LY294002 caused increased apoptosis, cell cycle, and cell growth arrest in HCT-116 cells. Inhibition of GSK-3beta, which is negatively regulated by AKT, using AR-A014418 and lithium chloride completely abolished LY294002-induced NAG-1 expression as well as the NAG-1 promoter activity. Furthermore, the down-regulation of GSK-3 gene using small interference RNA resulted in a decline of the NAG-1 expression in the presence of LY294002. These data suggest that expression of NAG-1 is regulated by PI3K/AKT/GSK-3beta pathway in HCT-116 cells and may provide a further understanding of the important role of PI3K/AKT/GSK-3beta pathway in tumorigenesis.
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PMID:Identification of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) as a novel downstream target of phosphatidylinositol 3-kinase/AKT/GSK-3beta pathway. 1537 73

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions with seven-transmembrane G-protein-coupled receptors (GPCRs) and the nuclear hormone receptor PPARgamma. To identify receptor-selective LPA analogues, we describe a series of fluorinated LPA analogues in which either the sn-1 or sn-2 hydroxyl group was replaced by a fluoro or fluoromethyl substituent. We also describe stabilized phosphonate analogues in which the bridging oxygen of the monophosphate was replaced by an alpha-monofluoromethylene (-CHF-) or alpha-difluoromethylene (-CF(2)-) moiety. The sn-2- and sn-1-fluoro-LPA analogues were unable to undergo acyl migration, effectively "freezing" them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively. We first tested these LPA analogues on insect Sf9 cells induced to express human LPA(1), LPA(2), and LPA(3) receptors. While none of the analogues were found to be more potent than 1-oleoyl-LPA at LPA(1) and LPA(2), several LPA analogues were potent LPA(3)-selective agonists. In contrast, 1-oleoyl-LPA had similar activity at all three receptors. The alpha-fluoromethylene phosphonate analogue 15 activated calcium release in LPA(3)-transfected insect Sf9 cells at a concentration 100-fold lower than that of 1-oleoyl-LPA. This activation was enantioselective, with the (2S)-enantiomer showing 1000-fold more activity than the (2R)-enantiomer. Similar results were found for calcium release in HT-29 and OVCAR8 cells. Analogue 15 was also more effective than 1-oleoyl-LPA in activating MAPK and AKT in cells expressing high levels of LPA(3). The alpha-fluoromethylene phosphonate moiety greatly increased the half-life of 15 in cell culture. Thus, alpha-fluoromethylene LPA analogues are unique new phosphatase-resistant ligands that provide enantiospecific and receptor-specific biological readouts.
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PMID:Structure-activity relationships of fluorinated lysophosphatidic acid analogues. 1585 37

Ischemic preconditioning, the most powerful protection against infarction, activates PI3Kinase (PI3K)/AKT and P42/44MAPK. Pioglitazone, a thiazolidinedione and PPARgamma receptor agonist used in Type II diabetes treatment, has been shown to activate these kinase cascades. We therefore hypothesized that pioglitazone could protect the myocardium when given prior to myocardial ischemia/reperfusion injury. Langendorff perfused rat hearts underwent 40 minutes of stabilization then 35 minutes of regional ischemia and 120 minutes of reperfusion (control) or Pioglitazone (1, 2, 5, and 10 microM)-given before ischemia. Additional groups underwent the same protocol but with either PI3K inhibitors (15 microM LY294002 or 100 nM wortmannin) or P42/44MAPK inhibitors (10 microM U0126 or 10 microM PD98059) given either during stabilization or at reperfusion. Infarct size was determined as a percentage of risk zone (I/R%). Pioglitazone (2 microM) significantly reduced I/R% compared with control (25.4 +/- 3.1 versus 47.3 +/- 3.4; P < 0.05). This protection was abolished by PI3K inhibitors (pioglitazone+LY294002 46.5 +/- 5.0, pioglitazone + wortmannin 48.8 +/- 4.6 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05) but not by P42/44MAPK inhibitors (pioglitazone+U0126 30.7 +/- 5.7, pioglitazone + PD98059 28.5 +/- 6.3 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05) given in stabilization. However when the inhibitors were given at reperfusion, the protection was abrogated by blocking either pathway (pioglitazone+LY294002 49.8 +/- 3.1, pioglitazone+U0126 48.7 +/- 3.7 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05). In conclusion pioglitazone induced significant protection against ischemia/reperfusion injury when administered prior to ischemia. This protection appears to involve PI3K and P42/44MAPK.
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PMID:Pioglitazone mimics preconditioning in the isolated perfused rat heart: a role for the prosurvival kinases PI3K and P42/44MAPK. 1630 7

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease.
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PMID:Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. 1642 25

Retinal pigment epithelial (RPE) cells constitute the external part of the blood-retinal-barrier and play a pivotal role in the regulation of retinal immunity. In the present work, we investigated the effects of 15-deoxy-12,14-prostaglandin J2 (15 PGJ2), an endogenous ligand of PPARgamma, on the IFNgamma-induced expression of MHC class II on RPE cells. Indeed, pathological expression of MHC class II molecules at the surface of RPE cells is a common feature of many blinding conditions. We demonstrated that 15 PGJ2 inhibited the IFNgamma-mediated induction of MHC class II on RPE cells without affecting the level of MHC class I and CD54 expression. The other PPARgamma agonist rosiglitazone or troglitazone had no similar effects. Moreover, the inhibitory effect of 15 PGJ2 was not abrogated by co-incubation with PPARgamma antagonists and did not involve the modulation of STAT-1, AKT or ERK1/2 phosphorylation, nor CIITA, IRF1 or IRF2 transcription. In conclusion, 15 PGJ2 inhibits strongly and specifically the IFNgamma-induced MHC class II expression on RPE cells by a PPARgamma independent mechanism. Given the differential role of MHC classes I and II in the development of autoimmune uveitis and the potential toxicity of 15 PGJ2, our data's suggest that the development of novel small molecules targeting similar PPARgamma independent pathways would be useful for the future management of uveitis.
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PMID:15-Deoxy-12,14-prostaglandin J2 inhibits interferon gamma induced MHC class II but not class I expression on ARPE cells through a PPAR gamma independent mechanism. 1693 78

An efficient stereocontrolled synthesis afforded alkoxymethylenephosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP-LPA and MP-PA analogues were characterized for LPA receptor subtype-specific agonist and antagonist activity using Ca(2+)-mobilization assays in RH7777 cells expressing the individual LPA(1)-LPA(3) receptors and CHO cells expressing LPA(4). In addition, activation of a PPARgamma reporter gene construct expressed in CV-1 cells was assessed. These metabolically stabilized LPA analogues exhibited an unexpected pattern of partial agonist/antagonist activity for the LPA G-protein-coupled receptor family and the intracellular LPA receptor PPARgamma. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT-29 colon cancer cells, which exclusively express LPA(2), and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA(1), LPA(2), and LPA(3). Unexpectedly, reverse phase protein arrays showed that four MP-LPA and MP-PA analogues selectively activated downstream signaling in HT-29 cells with greater potency than LPA. In particular, the oleoyl MP-LPA analogue strongly promoted phosphorylation and activation of AKT, MEK, and pS6 in HT-29 cells in a concentration-dependent manner. In contrast, the four MP-LPA and MP-PA analogues were equipotent with LPA for pathway activation in the SKOV3 and OVCAR3 cells. Taken together, these results suggest that the MP analogues may selectively activate signaling via the LPA(2) receptor subtype, while simultaneously suppressing signaling through the LPA(1) and LPA(3) subtypes.
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PMID:Alkoxymethylenephosphonate analogues of (Lyso) phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor. 1795 80

In the present study, we assessed that cilostazol stimulates differentiation of 3T3-L1 fibroblasts into adipocytes, and to improve insulin sensitivity in conjunction with PPARgamma transcriptional activity. Upon treatment of COS-7 cells and human umbilical vein endothelial cells (HUVECs) with cilostazol (10 and 30 microM), endogenous PPARgamma transcriptional activity was significantly elevated in both cells as did rosiglitazone (10 microM), and these effects were suppressed by 5 microM GW9662, an antagonist of PPARgamma activity. Cilostazol-induced 3T3-L1 fibroblast differentiation into adipocytes in concert with increases in expression of PPARgamma responsive genes such as CCAAT enhancer binding protein alpha (C-EBPalpha), aP2, which were accompanied by increased adiponectin and decreased resistin expressions as did rosiglitazone. These variables were strongly suppressed by GW9662, indicative of a PPARgamma-mediated signaling. GLUT4 protein expression and glucose uptake were significantly elevated by cilostazol as was by rosiglitazone, which were also attenuated by GW9662, indicative of improvement of insulin sensitivity. Signaling pathways involved in the cilostazol-stimulated PPARgamma transcription activity in HUVECs included phosphatidylinositol 3-kinase (PI3-kinase)/AKT. Taken together, it is suggested that cilostazol increases differentiation of 3T3-L1 fibroblasts into adipocytes, and improves insulin sensitivity by stimulating PPARgamma transcription.
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PMID:Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-gamma transcription. 1835 28


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