Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine the regulation of type IV collagenase expression in murine peritoneal macrophages (PEM) after they are incubated with LPS. LPS stimulated the production of the latent forms of 92-kDa (MMP-9) and 72-kDa (MMP-2) type IV gelatinases in a dose-dependent (> 10 ng/ml) and serum-dependent manner. Time course analyses revealed that LPS regulated the expression of MMP-9 and MMP-2 via discordant kinetics. Prolonged treatment of PEM with LPS decreased MMP-9 but not MMP-2 activities. IFN-gamma decreased the production of both gelatinases by PEM responding to LPS. TGF-beta stimulated production of both matrix metalloproteinases but blocked the LPS-mediated secretion of MMP-9. LPS-stimulated MMP-9 production was suppressed by genistein and tyrphostin, two specific tyrosine kinase inhibitors, as well as H-7, a serine/threonine protein kinase inhibitor, but not by HA1004, a relatively selective inhibitor for PKA and PKG. Our data demonstrate that the secretion of MMP-2 and MMP-9 by murine PEM is differentially regulated, suggesting a distinct in vivo role for these two otherwise analogous type IV gelatinases in macrophage-mediated connective tissue destruction at sites of immunologic challenges.
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PMID:Regulatory mechanisms for the expression of type IV collagenases/gelatinases in murine macrophages. 814 39

Culture of mesangial cells (MCs) in 5.6 vs. 30.0 mmol/l glucose for 3 weeks induced a sustained increase in protein kinase C (PKC) activity, transforming growth factor (TGF)-beta1 mRNA, bioactive TGF-beta, and collagen synthesis. Nitric oxide (NO), generated exogenously by the NO donor S-nitroso-N-acetyl, D,L-penicillamine (SNAP) or endogenously after the exposure of MC to interleukin-1beta (IL-1beta), suppressed bioactive TGF-beta in MCs cultured in 5.6 or 30.0 mmol/l glucose and suppressed or abolished increases in TGF-beta1 mRNA and collagen synthesis induced by high concentrations of glucose or phorbol 12,13-dibutyrate without altering values obtained with normal glucose concentrations. SNAP had a transient suppressive effect on PKC activity, which may explain at least in part some of the actions of SNAP. The selective inhibitor of PKC, bisindolylmaleimide (GFX), mimicked NO action. The ability of SNAP and IL-1beta to suppress TGF-beta and collagen synthesis was not mediated by cGMP, since the cGMP analog, 8-Br-PET-cGMP, did not mimic NO action and an antagonist of cGMP-dependent protein kinase, Rp-8-pCPT-cGMPs, did not prevent the inhibitory actions of SNAP. N-omega-L-arginine methyl ester (NMMA) increased TGF-beta in glomerular capillary endothelial cells (GCECs) and stimulated collagen synthesis by MC in a co-culture with GCECs. Captopril inhibited TGF-beta and collagen synthesis and increased cGMP in co-cultures of GCECs and MCs. These effects of captopril were abolished by NMMA, implying mediation by NO. Thus, endogenous NO produced by GCECs may modulate TGF-beta production by both GCECs and MCs and act to suppress matrix protein synthesis by MCs.
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PMID:Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. 907 10

In this study we report about the modulation of connexin45 (Cx45) gap junction channel properties by phosphorylation of the connexin molecules through different protein kinases. Phosphorylation of Cx45 was studied in HeLa cells transfected with mouse Cx45 (mCx45). Using Western blotting (WB) and immunocytochemistry, these cells were found exclusively positive for Cx45 and the protein was separated as a doublet of bands with a calculated mass of 46 and 48 kD. After dephosphorylation using calf intestine phosphatase (CIP), the 48 kD band disappeared almost completely leaving a single band at 46 kD. This effect can be prevented by including phosphatase inhibitors during CIP treatment. These results indicate that the 48 kD signal represents a phosphorylated form of Cx45. To investigate the effects of (de)phosphorylation of Cx45 on the conductive properties of gap junction channels built of this connexin, cell pairs were subjected to dual voltage clamp experiments and coupling was determined before and after addition of PMA, 4alpha-PDD, cAMP, cGMP, and pervanadate to the superfusate. 100 nM of the PKC activating phorbol ester PMA increased normalized junctional conductance by 50.9+/-28%. 100 nM of the inactive phorbol ester 4alpha-PDD had no significant effect. Activation of PKA with 1 mM 8-Br-cAMP decreased coupling by 20.9+/-5.7% while 1 mM 8-Br-cGMP (PKG-activation) was ineffective. 100 microM pervanadate, a tyrosine phosphatase inhibitor, reduced coupling by 43.7+/-11.1%. Single channel measurements, under identical phosphorylating conditions, were not significantly different from each other and all frequency histograms exhibited two conductance peaks at approximately 20 and 40 pS. WB analysis revealed, as compared to control conditions, a relative increase of the 48 kD signal upon stimulation with pervanadate (142+/-42%) and 8-Br-cAMP (50+/-23%) whereas neither stimulation with PMA nor 8-Br-cGMP had a significant effect. These experiments show that electrical intercellular conductance via Cx45 gap junction channels is differentially regulated by phosphorylation. However, regulation does not act by changing single channel conductance, but most likely by modulation of the open probability of Cx45 gap junction channels.
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PMID:Electrical conductance of mouse connexin45 gap junction channels is modulated by phosphorylation. 1091 60

Hyperglycemia is a crucial factor in the development of diabetic nephropathy. We previously showed that high glucose upregulates thrombospondin 1 (TSP1)-dependent transforming growth factor (TGF)-beta activation by altering cGMP-dependent protein kinase (PKG) activity as a result of decreased nitric oxide signaling. In the present study, we showed that high glucose concentrations significantly reduced endogenous PKG activity. To further examine the mechanisms by which PKG regulates TSP1 expression and TSP1-dependent TGF-beta activation, we generated stably transfected rat mesangial cells (RMCs) with inducible expression tetracycline-induced gene expression of the catalytic domain of PKG. After tetracycline induction, the catalytic domain of PKG is expressed as a cGMP-independent active kinase. Expression of the catalytic domain prevented high glucose-mediated increases in transcription of the TSP1 gene with no alteration in TSP1 mRNA stability. Glucose stimulation of TSP1 protein expression and TGF-beta bioactivity were also downregulated. TGF-beta-dependent fibronectin and type IV collagen expression under high glucose conditions were significantly reduced upon catalytic domain expression in transfected RMCs. These results show that constitutively active PKG inhibits the fibrogenic potential of high glucose through repression of TSP1-dependent TGF-beta bioactivity, suggesting that gene transfer of the catalytic domain of PKG might provide a new strategy for treatment of diabetic renal fibrosis.
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PMID:Expression of constitutively active cGMP-dependent protein kinase prevents glucose stimulation of thrombospondin 1 expression and TGF-beta activity. 1288 34

Thrombospondin 1 (TSP1) transcription is stimulated by glucose, resulting in increased TGF-beta activation and matrix protein synthesis. We previously showed that inducible expression of the catalytic domain of cGMP-dependent protein kinase (PKG) inhibits glucose-regulated TSP1 transcription and transforming growth factor (TGF)-beta activity in stably transfected rat mesangial cells (RMCs(tr/cd)). However, the molecular mechanisms by which PKG represses glucose-regulated TSP1 transcription are unknown. Using a luciferase-promoter deletion assay, we now identify a single region of the human TSP1 promoter (-1172 to -878, relative to the transcription start site) that is responsive to glucose. Further characterization of this region identified an 18-bp sequence that specifically binds nuclear proteins from mesangial cells. Moreover, binding is significantly enhanced by high glucose treatment and is reduced by increased PKG activity. Gel mobility shift and supershift assays show that the nuclear proteins binding to the 18-bp sequence are USF1 and -2. USF1 and USF2 bound to the endogenous TSP1 promoter using a chromatin immunoprecipitation assay. Glucose stimulates nuclear USF2 protein accumulation through protein kinase C, p38 MAPK, and extracellular signal-regulated kinase pathways. Increased PKG activity down-regulates USF2 protein levels and its DNA binding activity under high glucose conditions, resulting in inhibition of glucose-induced TSP1 transcription and TGF-beta activity. Overexpression of USF2 reversed the inhibitory effect of PKG on glucose-induced TSP1 gene transcription and TGF-beta activity. Taken together these data present the first evidence that USF2 mediates glucose-induced TSP1 expression and TSP1-dependent TGF-beta bioactivity in mesangial cells, suggesting that USF2 is an important transcriptional regulator of diabetic complications.
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PMID:Glucose up-regulates thrombospondin 1 gene transcription and transforming growth factor-beta activity through antagonism of cGMP-dependent protein kinase repression via upstream stimulatory factor 2. 1518 88

The osteoclast is a monocyte-derived cell with complex regulatory control due to its role, balancing calcium homeostasis with skeletal modelling and repair. Normal differentiation requires tyrosine kinase- and tumor necrosis-family receptors, normally fms and RANK. Ligands for these receptors plus unidentified serum or cell-presented factor(s) are needed for in vitro differentiation, possibly signalling via an immune-like tyrosine kinase acceptor molecule. Osteoclast development and activity are increased by cytokines signalling through GP130, such as IL-6, by TGF-beta, and by IL-1, although these cannot replace serum. Other tyrosine kinase receptors including kit and met can augment fms signalling, and TNFs other than RANKL, including TNFalpha and TRAIL, modify RANK signalling, which is also susceptible to interference by interferons. The situation is further complicated by G-protein coupled receptors including the calcitonin receptor, by integrin or calcium-mediated signals, and by estrogen receptors, which operate in bone largely via NO downstream signals. Differentiation, activity, and survival signals merge in intracellular second messengers. These include cytoplasmic kinases of several families; differentiation pathways often terminate in Erk/Jun kinases or NF-kappaB. Key regulatory intermediates include TRAF6, src, Smad3, phosphatidylinositol-3-kinase, Jak/Stat, and the cGMP-dependent protein kinase I. There are substantial uncertainties regarding how intracellular agents connect to primary signals. The frontier includes characterization of how scaffolding/adapter proteins, such as cbl, gab, grb, p130Cas, and shc, as well as itam-containing proteins and nonreceptor tyrosine kinase adapters of the src and syk families, delimit and integrate signals of multiple receptors to bring about specific outcomes.
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PMID:Osteoclast signalling pathways. 1569 7

Many forms of vascular disease are characterized by increased transforming growth factor (TGF)-beta1 expression and endothelial dysfunction. Smad proteins are a key step in TGF-beta-initiated signal transduction. We hypothesized that NO may regulate endothelial TGF-beta-dependent gene expression. We show that NO inhibits TGF-beta/Smad-regulated gene transactivation in a cGMP-dependent manner. NO effects were mimicked by a soluble analogue of cGMP. Inhibition of cGMP-dependent protein kinase 1 (PKG-1) or overexpression of dominant-negative PKG-1alpha suppressed NO/cGMP inhibition of TGF-beta-induced gene expression. Inversely, overexpression of PKG-1alpha catalytic subunit blocked TGF-beta-induced gene transactivation. Furthermore NO delayed and reduced phosphorylated Smad2/3 nuclear translocation, an effect mediated by PKG-1, whereas NG-nitro-L-arginine methyl ester augmented Smad phosphorylation and gene expression in response to TGF-beta. Aortas from endothelial NO synthase-deficient mice showed enhanced basal TGF-beta1 and collagen type I expression; endothelial cells from these animals showed increased Smad phosphorylation and transcriptional activity. Proteasome inhibitors prevented the inhibitory effect of NO on TGF-beta signaling. NO reduced the metabolic life of ectopically expressed Smad2 and enhanced its ubiquitination. Taken together, these results suggest that the endothelial NO/cGMP/PKG pathway interferes with TGF-beta/Smad2 signaling by directing the proteasomal degradation of activated Smad.
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PMID:Nitric oxide regulates transforming growth factor-beta signaling in endothelial cells. 1630 52

Despite the prevalence of obesity and its related diseases, the signaling pathways for appetite control and satiety are not clearly understood. Here we report C. elegans quiescence behavior, a cessation of food intake and movement that is possibly a result of satiety. C. elegans quiescence shares several characteristics of satiety in mammals. It is induced by high-quality food, it requires nutritional signals from the intestine, and it depends on prior feeding history: fasting enhances quiescence after refeeding. During refeeding after fasting, quiescence is evoked, causing gradual inhibition of food intake and movement, mimicking the behavioral sequence of satiety in mammals. Based on these similarities, we propose that quiescence results from satiety. This hypothesized satiety-induced quiescence is regulated by peptide signals such as insulin and TGF-beta. The EGL-4 cGMP-dependent protein kinase functions downstream of insulin and TGF-beta in sensory neurons including ASI to control quiescence in response to food intake.
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PMID:Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety. 1831 30

Thrombospondins (TSPs) are multifunctional matricellular glycoproteins which are involved in the regulation of angiogenesis, proliferation, apoptosis, the NO-cGMP-dependent protein kinase pathway and transforming growth factor (TGF) beta activation. The TSP family consists of 5 members, but currently only data on effects of TSP-1 and TSP-2 in renal disease are available. Both TSPs are hardly expressed within the healthy renal cortex and can be upregulated during renal disease. Using different animal models for renal disease, TSP-1 and -2 were found to be important regulators of pathophysiological changes during renal disease with similar and contrary effects. TSP-1 is a major activator for TGF-beta resulting in profibrotic effects in the injured kidney. In contrast, TSP-2 lacks the ability for its activation. Proapoptotic actions of TSP-1 were found during renal ischemia/reperfusion injury. While TSP-1 exerts proinflammatory actions, the currently available data for TSP-2 propose anti-inflammatory effects for this molecule. Both TSPs are known angiogenesis inhibitors, which could be proved for TSP-2, but antiangiogenic effects for TSP-1 were only evident by treatment with TSP-1 peptides in renal disease. In addition, TSP-2 can inhibit cell proliferation and matrix metalloproteinase 2 activity.
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PMID:Thrombospondin in renal disease. 1918 92

The aim of the present study was to test the hypothesis that the TRPV4-NO-cGMP-PKG cascade is involved in the maintenance of thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rats. CCD rats showed thermal hyperalgesia and increased nitrite production. Intrathecal administration of ruthenium red (TRPV4 antagonist, 0.1-1 nmol), TRPV4 antisense ODN (TRPV4 AS, 40 microg, daily for 7 days), N(G)-L-nitro-arginine methyl ester (l-NAME, inhibitor of NO synthase, 30-300 nmol), 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor, 50-100 nmol) or 8-(4-Chlorophenylthio) guanosine 3',5'-cyclic Monophosphothioate, Rp-Isomer sodium salt (Rp-8-pCPT-cGMPS, a PKG inhibitor, 25-50 nmol) induced a significant (P<0.001) and dose-dependent increase in the paw withdrawal latency (PWL) compared with control rats, respectively. Ruthenium red (1 nmol), TRPV4 AS (40 microg, daily for 7 days) or L-NAME (300 nmol) decreased nitrite (an index of nitric oxide formation) in the DRG of CCD rats. In addition, the phorbol ester 4alpha-phorbol 12,13-didecanoate (4alpha-PDD, TRPV4 synthetic activator, 1 nmol), co-administered with L-NAME (300 nmol), attenuated the suppressive effect of L-NAME on CCD-induced thermal hyperalgesia and nitrite production. Our data suggested that the TRPV4-NO-cGMP-PKG pathway could be involved in CCD-induced thermal hyperalgesia.
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PMID:Involvement of TRPV4-NO-cGMP-PKG pathways in the development of thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats. 1994 93


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