Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display notable similarities as well as differences. HO and NOS are both oxidative enzymes using NADPH as an electron donor. The constitutive forms of the enzyme are differentially activated, with calcium entry stimulating NOS by binding to calmodulin, whereas calcium entry activates protein kinase C to phosphorylate and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets. Both involve constitutive and inducible biosynthetic enzymes. However, functions of the inducible forms are virtual opposites. Macrophage-inducible NOS generates NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's N-methyl-d-aspartate receptor activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO2, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system. They also are physiologic endothelial-derived relaxing factors for blood vessels. In the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth muscle relaxation.
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PMID:Neural roles for heme oxygenase: contrasts to nitric oxide synthase. 1157 59

Heme-hemopexin coordinately regulates genes encoding protective proteins including metallothionein-I (MT-I) and heme oxygenase 1 (HO-1). Hexamethylene-bisacetamide (HMBA), which induces differentiation and activates protein kinase C (PKC), synergistically augments the induction of both MT-I and MT-II mRNAs in response to heme-hemopexin, but attenuates the induction of HO-1. HMBA also augments the increase in MT mRNA in response to cobalt protoporphyrin-hemopexin, a hemopexin (HPX) receptor ligand that activates signaling cascades without tetrapyrrole uptake. Unlike the PKC-activating phorbol esters that induce MT-I and HO-1, HMBA has minimal effects on MT-I or HO-1. HMBA is an amphipathic molecule, and is shown here to interact physically with lipids in model membranes using differential scanning calorimetry (DSC). The data are consistent with a stabilization of the lipid bilayer and an HMBA-induced segregation of lipids into separate domains each relatively enriched in one of the lipids. HMBA also perturbs membrane-protein interactions, and causes a loss of PKC and G-protein subunits from plasma membranes in vitro. Taken together, these observations reveal an additional level of complexity in the regulation of protective proteins induced by HPX, and which may take place in vivo in response to natural compounds that reorganize membrane phospholipids. A model is proposed whereby a reorganization of lipids by HMBA alters signaling pathways and fusion events considered to be the etiology of the differential response of the MT-1 (and MT-II) and the HO-1 genes to HMBA and heme-HPX.
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PMID:Membrane phospholipid reorganization differentially regulates metallothionein and heme oxygenase by heme-hemopexin. 1204 74

Physiologically, angiogenesis is tightly regulated, or otherwise it leads to pathological processes, such as tumors, inflammatory diseases, gynecological diseases and diabetic retinopathy. The vascular endothelial growth factor (VEGF) is a potent and critical inducer of angiogenesis. The VEGF gene expression is regulated by a variety of stimuli. Hypoxia is one of the most potent inducers of the VEGF expression. The hypoxia inducible factor 1 (HIF-1) plays as a key transcription factor in hypoxia-mediated VEGF gene upregulation. Nitric oxide (NO) as well as hypoxia is reported to upregulate the VEGF gene by enhancing HIF-1 activity. The Akt/protein kinase B (PKB) pathway may be involved in NO-mediated HIF-1 activation in limited cell lines. There are some reports of negative effects of NO on HIF-1 and VEGF activity. These conflicting data of NO effects may be attributed mainly to the amount of released NO. Indeed, NO can be a positive or negative modulator of the VEGF gene under the same conditions simply by changing its amounts. The VEGF-mediated angiogenesis requires NO production from activated endothelial NO synthase (eNOS). Activation of eNOS by VEGF involves several pathways including Akt/PKB, Ca(2+)/calmodulin, and protein kinase C. The NO-mediated VEGF expression can be regulated by HIF-1 and heme oxygenase 1 (HO-1) activity, and the VEGF-mediated NO production by eNOS can be also modulated by HIF-1 and HO-1 activity, depending upon the amount of produced NO. These reciprocal relations between NO and VEGF may contribute to regulated angiogenesis in normal tissues.
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PMID:Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis. 1267 46

Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of antioxidative proteins, including heme oxygenase-1 (HO-1). Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element (ARE) upon exposure to oxidative insults. It has recently been demonstrated that in vitro phosphorylation of Nrf2 on Ser40 by protein kinase C (PKC) facilitates the dissociation of Nrf2 from the Keap1 complex (Huang HC, Nguyen T, and Pickett CB. J Biol Chem 277: 42769-42774, 2002). The present study was designed to examine whether PKC is involved in oxidative stress-mediated nuclear translocation of Nrf2 in vivo and, if so, which PKC isoforms are involved. Induction of HO-1 gene expression by phorone, a glutathione depletor, and 4-hydroxy-2,3-nonenal (4-HNE), an end product of lipid peroxidation, was suppressed by a specific PKC inhibitor, Ro-31-8220, at concentrations that inhibit all isoforms in WI-38 cells. The induction of HO-1 was not affected by prolonged exposure of the cells to 12-O-tetradecanoylphorbol-13 acetate (TPA), suggesting that TPA-insensitive atypical PKC (aPKC) isoforms are involved. An immunocomplex kinase assay revealed that phorone and 4-HNE increased aPKCiota activity. In COS-7 cells, 4-HNE induced nuclear translocation of the Nrf2-green fluorescent protein (GFP) fusion protein, but not the Nrf2(S40A)-GFP mutant. In the absence of oxidative insults, the Nrf2(S40E)-GFP mutant was distributed in the nucleus. The Nrf2-GFP accumulation in the nucleus was induced by coexpression of aPKCiota, but not by a kinase inactive mutant aPKCiota(K274W). The activity of an ARE-driven reporter was increased by coexpression of aPKCiota, and this effect was eliminated by Ro-31-8220 in HepG2 cells. The reporter activity induced by 4-HNE was inhibited by coexpression of aPKCiota(K274W). These results suggest that phosphorylation of Nrf2 Ser40 by aPKC(s) is involved in the nuclear translocation and ARE transactivation of Nrf2 by oxidative stress.
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PMID:Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. 1270 Jan 36

(1) Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. It has been recently suggested that the inducible heme oxygenase (HO-1) isoform may play a role in angiogenesis. (2) The aims of this study were to determine, in chicken embryo chorioallantoic membranes (CAM), whether VEGF increases HO-1 protein expression, and, if so, by which molecular mechanism, and whether HO-1 activity is required for VEGF-induced angiogenesis. (3) Treatment of CAMs with VEGF for 48 h caused a significant increase in HO-1 protein expression, simultaneously with angiogenesis. (4) VEGF-stimulated angiogenesis in CAMs was markedly attenuated by the HO inhibitor zinc mesoporphyrin (ZnMP). This inhibitory effect of ZnMP was not observed with copper mesoporphyrin (CuMP), a metalloporphyrin that has a similar structure to ZnMP but does not inhibit HO enzymatic activity. (5) Overexpression of HO-1 protein elicited by VEGF in CAMs was significantly attenuated by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). The effects of BAPTA-AM were, in turn, compensated by the calcium ionophore A-23187. (6) In addition, the protein kinase C inhibitor staurosporine significantly attenuated, in a dose-dependent manner, the VEGF-stimulated HO-1 induction observed in CAMs. (7) These results demonstrate, for the first time, that VEGF upregulates HO-1 protein expression in vivo in CAMs by a mechanism dependent on an increase in cytosolic calcium levels and activation of protein kinase C. Our findings also suggest that HO-1 activity is necessary for VEGF-induced angiogenesis in CAMs.
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PMID:Vascular endothelial growth factor increases heme oxygenase-1 protein expression in the chick embryo chorioallantoic membrane. 1278 23

Ischemic preconditioning protects the kidney from subsequent ischemic injury but the signal transduction pathways involved are unknown. Human proximal tubular (HK-2) cells were protected from injury with 2.5 mM H(2)O(2) by preconditioning with a single 15-min exposure to 500 microM H(2)O(2) followed by 16 h of recovery (oxidant preconditioning). To identify the signaling pathways involved in oxidant preconditioning, we utilized inhibitors of several signaling intermediates (MAPK/ERK kinase I, p38 mitogen-activated protein kinase (MAPK), protein kinase C and tyrosine kinase). A rapid but transient increase in p38 MAPK was observed following oxidant preconditioning and an inhibitor of p38 MAPK (SB203580) abolished the protection provided by oxidant preconditioning. Oxidant preconditioning was also associated with heat shock protein-27 phosphorylation (by p38 MAPK) and an increased synthesis of heme oxygenase-1 (HO-1). Stimulation or inhibition of HO-1 with hemin or Zn(II) protoporphyrin IX, respectively, mimicked or abolished oxidant preconditioning-mediated cytoprotection. Inhibitors of new protein synthesis (cycloheximide) and gene transcription (actinomycin D) also blocked the cytoprotection by oxidant preconditioning. We conclude that oxidant preconditioning protects HK-2 cells against more severe oxidant injury via activation of signaling pathways that include p38 MAPK and increased synthesis of HO-1.
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PMID:Oxidant preconditioning protects human proximal tubular cells against lethal oxidant injury via p38 MAPK and heme oxygenase-1. 1291 76

Ischemia/reperfusion is the main cause of hepatic damage consequent to temporary clamping of the hepatoduodenal ligament during liver surgery as well as graft failure after liver transplantation. In recent years, a number of animal studies have shown that pre-exposure of the liver to transient ischemia, hyperthermia, or mild oxidative stress increases the tolerance to reperfusion injury, a phenomenon known as hepatic preconditioning. The development of hepatic preconditioning can be differentiated into 2 phases. An immediate phase (early preconditioning) occurs within minutes and involves the direct modulation of energy supplies, pH regulation, Na(+) and Ca(2+) homeostasis, and caspase activation. The subsequent phase (late preconditioning) begins 12-24 hours after the stimulus and requires the synthesis of multiple stress-response proteins, including heat shock proteins HSP70, HSP27, and HSP32/heme oxygenase 1. Hepatic preconditioning is not limited to parenchymal cells but ameliorates sinusoidal perfusion, prevents postischemic neutrophil infiltration, and decreases the production of proinflammatory cytokines by Kupffer cells. This latter effect is important in improving systemic disorders associated with hepatic ischemia/reperfusion. The signals triggering hepatic preconditioning have been partially characterized, showing that adenosine, nitric oxide, and reactive oxygen species can activate multiple protein kinase cascades involving, among others, protein kinase C and p38 mitogen-activated protein kinase. These observations, along with preliminary studies in humans, give a rationale to perform clinical trials aimed at verifying the possible application of hepatic preconditioning in preventing ischemia/reperfusion injury during liver surgery.
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PMID:Recent insights on the mechanisms of liver preconditioning. 1459 65

Scleroderma, a disease involving excessive collagen deposition, can be studied using fibroblasts cultured from affected tissues. We find that curcumin, the active component of the spice turmeric, causes apoptosis in scleroderma lung fibroblasts (SLF), but not in normal lung fibroblasts (NLF). This effect is likely to be linked to the fact that although curcumin induces the expression of the phase 2 detoxification enzymes heme oxygenase 1 and glutathione S-transferase P1 (GST P1) in NLF, SLF are deficient in these enzymes, particularly after curcumin treatment. The sensitivity of cells to curcumin-induced apoptosis and the expression of GST P1 (but not heme oxygenase 1) are regulated by the epsilon isoform of protein kinase C (PKCepsilon). SLF, which contain less PKCepsilon and less GST P1 than NLF, become less sensitive to curcumin-induced apoptosis and express higher levels of GST P1 when transfected with wild-type PKCepsilon, but not with dominant-negative PKCepsilon. Conversely, NLF become sensitive to curcumin-induced apoptosis and express lower levels of GST P1 when PKCepsilon expression or function is inhibited. The subcellular distribution of PKCepsilon also differs in NLF and SLF. PKCepsilon is predominantly nuclear or perinuclear in NLF but is associated with stress fibers in SLF. Just as PKCepsilon levels are lower in SLF than in NLF in vitro, PKCepsilon expression is decreased in fibrotic lung tissue in vivo. In summary, our results suggest that a signaling pathway involving PKCepsilon and phase 2 detoxification enzymes provides protection against curcumin-induced apoptosis in NLF and is defective in SLF. These observations suggest that curcumin may have therapeutic value in treating scleroderma, just as it has already been shown to protect rats from lung fibrosis induced by a variety of agents.
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PMID:Curcumin-induced apoptosis in scleroderma lung fibroblasts: role of protein kinase cepsilon. 1474 95

Atrial natriuretic peptide (ANP)-preconditioned livers are protected from ischemia-reperfusion injury. ANP-treated organs show increased expression of heme oxygenase (HO)-1. Because HO-1 liberates bound iron, the aim of our study was to determine whether ANP affects iron regulatory protein (IRP) activity and, thus, the levels of ferritin. Rat livers were perfused with Krebs-Henseleit buffer [+/-ANP, 8-bromo-cGMP (8-Br-cGMP), and tin protoporphyrin, 20 min], stored in University of Wisconsin solution (4 degrees C, 24 h), and reperfused (120 min). IRP activity was assessed by gel-shift assays, and ferritin, IRP phosphorylation, and PKC localization were assessed by Western blot. Control livers displayed decreased IRP activity at the end of ischemia but no change in ferritin content during ischemia and reperfusion. ANP-pretreated livers showed reduced IRP activity, an effect mimicked by 8-Br-cGMP. Ferritin levels were increased in ANP-pretreated organs. Simultaneous perfusion of livers with ANP and tin protoporphyrin did not reduce ANP-induced action, arguing against a role for HO-1 in changes in IRP activity. ANP and 8-Br-cGMP decreased membrane localization of PKC-alpha and PKC-epsilon, but this modulation of PKC seems unrelated to inhibition of IRP binding. This work shows the cGMP-mediated attenuation of IRP binding activity by ANP, which results in increased hepatic ferritin levels. This change in IRPs is independent of ANP-induced HO-1 and reduced PKC activation.
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PMID:ANP-induced decrease of iron regulatory protein activity is independent of HO-1 induction. 1508 80

Transient glucose deprivation (TGD) has been shown to induce a resistance to a subsequent ischemia and reperfusion injury in the heart. Induction of cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) is known to mediate the powerful defensive adaptation of the heart against oxidative stress. In this study, we found that a 30-min incubation in the absence of glucose resulted in a rapid increased expression of COX-2 and HO-1 in cardiac fibroblasts as examined by real-time quantitative polymerase chain reaction (PCR) and western blot analysis. Interestingly, TGD increased the generation of reactive oxygen species (ROS) and caused the transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as the translocation of protein kinase C (PKC)- from the cytosolic to the membrane fraction. However, no significant change in the distribution of PKC-delta isoform was observed compared with the control. Pretreatment of the cells with an antioxidant, N-acetylcysteine (NAC), resulted in the inhibition of p38 MAPK phosphorylation and PKC- translocation during TGD. In addition, the induction of COX-2 and HO-1 expression by TGD was prevented by pretreatment with NAC or SB203580, a p38 MAPK inhibitor. Surprisingly, pretreatment with chelerythrine, an inhibitor of PKC, strongly augmented the HO-1 mRNA expression but blocked the COX-2 mRNA induction by TGD. These results demonstrate that briefly removing glucose from cultured cardiac fibroblasts induces COX-2 and HO-1 expression via generation of ROS and p38 MAPK phosphorylation, while the translocation of PKC- to the membrane fraction may participate in the induction of COX-2 but not in the HO-1 expression.
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PMID:Transient glucose deprivation causes upregulation of heme oxygenase-1 and cyclooxygenase-2 expression in cardiac fibroblasts. 1515 23


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