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: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein phosphatase calcineurin is a signaling intermediate that induces the transformation of fast-twitch skeletal muscle fibers to a slow-twitch phenotype. This reprogramming of the skeletal muscle gene expression profile may have therapeutic applications for metabolic disease. Insulin-stimulated glucose uptake in skeletal muscle is both impaired in individuals with type II diabetes mellitus and positively correlated with the percentage of slow- versus fast-twitch muscle fibers. Using transgenic mice expressing activated calcineurin in skeletal muscle, we report that skeletal muscle reprogramming by calcineurin activation leads to improved insulin-stimulated 2-deoxyglucose uptake in extensor digitorum longus (EDL) muscles compared with wild-type mice, concomitant with increased protein expression of the insulin receptor, Akt, glucose transporter 4, and peroxisome proliferator-activated receptor-gamma co-activator 1. Transgenic mice exhibited elevated glycogen deposition, enhanced amino acid uptake, and increased fatty acid oxidation in EDL muscle. When fed a high-fat diet, transgenic mice maintained superior rates of insulin-stimulated glucose uptake in EDL muscle and were protected against diet-induced glucose intolerance. These results validate calcineurin as a target for enhancing insulin action in skeletal muscle.
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PMID:Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways. 1294 59

Arginine vasopressin (AVP) stimulates adrenocorticotropin (ACTH) secretion from corticotroph cells of the anterior pituitary via activation of the V1b vasopressin receptor, a member of the G protein-coupled receptor (GPCR) family. Recently, we have shown that treatment of ovine anterior pituitary cells with AVP for short periods results in reduced responsiveness to subsequent stimulation with AVP. The aim of this study was to investigate mechanisms involved in this desensitization process. Among the GPCR family, rapid desensitization is commonly mediated by receptor phosphorylation, with resensitization being mediated by internalization and subsequent dephosphorylation of the receptors by protein phosphatases. Since desensitization of V1a vasopressin receptors is mediated by protein kinase C-mediated receptor phosphorylation, we investigated the involvement of this enzyme in desensitization of the ACTH response to AVP. Treatment of perifused ovine anterior pituitary cells with the specific protein kinase C (PKC) activator 1,2-dioctanoyl-sn-glycerol (300 microM) did not induce any reduction in response to a subsequent 5-min stimulation with 100 nM AVP, despite potently stimulating ACTH secretion. Likewise, the results obtained using the PKC inhibitor Ro 31-8220 were not consistent with involvement of PKC in AVP desensitization: 2 microM Ro 31-8220 did not reduce the ability of a 10 nM AVP pretreatment to induce desensitization to a subsequent stimulation with 100 nM AVP. Pharmacologic blockade of receptor internalization by treatment with 0.25 mg/ml concanavalin A significantly impaired the ability of a 15-min pretreatment with 10 nM AVP to induce desensitization, rather than affecting resensitization. Treatment with 10 nM okadaic acid, an inhibitor of protein phosphatase 1 and 2A, had no effect on either resensitization or desensitization. In contrast, inhibition of protein phosphatase 2B (PP2B) with 1 microM FK506 decreased the rate of resensitization: complete recovery from desensitization took 40 min, whereas in controls recovery was complete 20 min after termination of the pretreatment. These results indicate that desensitization of the ACTH response to AVP is not mediated by PKC-catalyzed phosphorylation, suggesting subtype-specific differences in the regulation of V1a and V1b vasopressin receptors. The data demonstrate that desensitization was dependent, at least in part, upon receptor internalization and that resensitization was dependent upon PP2B-mediated receptor dephosphorylation.
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PMID:Mechanisms of desensitization of the adrenocorticotropin response to arginine vasopressin in ovine anterior pituitary cells. 1564 80

Pregnane X receptor (PXR, NR1I2) regulates the inducible expression of the 3A sub-family of cytochrome P450 genes (CYP3A). CYP3A enzymes are responsible for the oxidative metabolism of a wide array of endobiotic and xenobiotic compounds. Hepatic CYP3A gene expression is rapidly down-regulated during inflammation and sepsis. There are twelve protein kinase C (PKC) isoforms, classified into three subfamilies according to the structure of the N-terminal regulatory domain and their sensitivity to calcium and diacylglycerol. It is now well accepted that cytokine stimulation of hepatocytes increases intracellular PKC activity during inflammation and sepsis. We show here that protein kinase C alpha (PKC alpha) and phorbol ester-dependent PKC signaling dramatically repressed PXR activity in both, cell-based reporter gene assays and in hepatocytes. Moreover, treatment with the protein phosphatase PP1/PP2A inhibitor okadaic acid (OA) totally abolished PXR activity in reporter gene assays and in cultured hepatocytes. In mammalian two-hybrid assays, treatment with phorbol 12-myristate 13-acetate (PMA) increased the strength of interaction between PXR and the nuclear receptor co-repressor protein (NCoR). Treatment with PMA also abolished the ligand-dependent interaction between PXR and the steroid receptor co-activator 1 protein (SRC1). Our findings suggest that activation of the protein kinase C signaling pathway represses PXR activity through alterations in PXR-protein co-factor complexes, possibly through direct alterations in the phosphorylation status of one or all of these proteins. In addition, our data potentially provide important insights into the molecular mechanism of the repression of hepatic CYP3A gene expression that occurs during the inflammatory response.
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PMID:Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. 1571 Mar 63

Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon-gamma (IFN-gamma), which is a critical factor for immune surveillance of cancer and monocyte clearance of infection. We show that SET, which is a potent inhibitor of protein phosphatase type 2A (PP2A) activity, is highly expressed in human CD56bright NK cells, which produce more IFN-gamma than CD56dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN-gamma gene expression in monokine-stimulated NK cells. In contrast, RNAi-mediated suppression of SET expression renders NK cells inefficient in producing high levels of IFN-gamma in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN-gamma gene expression in NK cells. In fact, treatment of primary human NK cells with the PP2A activator 1,9-dideoxy-forskolin, as well as administration of the drug to C57BL/6 mice, significantly reduced NK-dependent IFN-gamma production in response to monokine treatment. Further, SET knockdown or pharmacologic activation of PP2A diminished extracellular signal-regulated kinase 1/2, p65RelA, signal transducer and activator of transduction 4 (STAT4), and STAT5 activity in monokine-stimulated NK cells, potentially contributing to the reduction in IFN-gamma gene expression. Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-gamma.
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PMID:The PP2A inhibitor SET regulates natural killer cell IFN-gamma production. 1787 74

The ability of natural killer (NK) cells to kill malignant or infected cells depends on the integration of signals from different families of cell surface receptors, including cytokine receptors. How such signals then regulate NK-cell cytotoxicity is incompletely understood. Here we analyzed an endogenous inhibitor of protein phosphatase 2A (PP2A) activity called SET, and its role in regulating human NK-cell cytotoxicity and its mechanism of action in human NK cells. RNAi-mediated suppression of SET down-modulates NK-cell cytotoxicity, whereas ectopic overexpression of SET enhances cytotoxicity. SET knockdown inhibits both mRNA and protein granzyme B expression, as well as perforin expression, whereas SET overexpression enhances granzyme B expression. Treatment of NK cells with the PP2A activator 1,9-dideoxy-forskolin also inhibits both granzyme B expression and cytotoxicity. In addition, pretreatment with the PP2A inhibitor okadaic acid rescues declining granzyme B mRNA levels in SET knockdown cells. Down-modulation of SET expression or activation of PP2A also decreases human NK-cell antibody-dependent cellular cytotoxicity. Finally, the induction of granzyme B gene expression by interleukin-2 and interleukin-15 is inhibited by SET knockdown. These data provide evidence that granzyme B gene expression and therefore human NK-cell cytotoxicity can be regulated by the PP2A-SET interplay.
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PMID:The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells. 2135 56

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca(2+) transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB's activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands.
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PMID:Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1. 2162 92

First identified as a dedicated CREB (cAMP response element-binding protein) co-activator, CRTC1 (CREB-regulated transcription co-activator 1) has been widely implicated in various neuronal functions because of its predominant expression in the brain. However, recent evidences converge to indicate that CRTC1 is aberrantly activated in an expanding number of adult malignancies. In this study, we provide strong evidences of enhanced CRTC1 protein content and transcriptional activity in mouse models of sporadic (APC(min/+) mice) or colitis-associated colon cancer azoxymethane/dextran sulfate sodium (AOM/DSS-treated mice), and in human colorectal tumors specimens compared with adjacent normal mucosa. Among signals that could trigger CRTC1 activation during colonic carcinogenesis, we demonstrate that treatment with cyclooxygenase 2 (COX2) inhibitors reduced nuclear CRTC1 active form levels in colonic tumors of APC(min/+) or AOM/DSS mice. In accordance, prostaglandins E2 (PGE2) exposure to human colon cancer cell lines promoted CRTC1 dephosphorylation and parallel nuclear translocation, resulting in enhanced CRTC1 transcriptional activity, through EP1 and EP2 receptors signaling and consecutive calcineurin and protein kinase A activation. In vitro CRTC1 loss of function in colon cancer cell lines was associated with reduced viability and cell division rate as well as enhanced chemotherapy-induced apoptosis on PGE2 treatment. Conversely, CRTC1 stable overexpression significantly increased colonic xenografts tumor growth, therefore demonstrating the role of CRTC1 signaling in colon cancer progression. Identification of the transcriptional program triggered by enhanced CRTC1 expression during colonic carcinogenesis, revealed some notable pro-tumorigenic CRTC1 target genes including NR4A2, COX2, amphiregulin (AREG) and IL-6. Finally, we demonstrate that COX2, AREG and IL-6 promoter activities triggered by CRTC1 are dependent on functional AP1 and CREB transcriptional partners. Overall, our study establishes CRTC1 as new mediator of PGE2 signaling, unravels the importance of its dysregulation in colon cancer and strengthens its use as a bona fide cancer marker.
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PMID:Dysregulated CRTC1 activity is a novel component of PGE2 signaling that contributes to colon cancer growth. 2630 3

Mitochondria are responsible for aerobic respiration and large-scale ATP production in almost all cells of the body. Their function is decreased in many neurodegenerative and cardiovascular disease states, in metabolic disorders such as type II diabetes and obesity, and as a normal component of aging. Disuse of skeletal muscle from immobilization or unloading triggers alterations of mitochondrial density and activity. Resultant mitochondrial dysfunction after paralysis, which precedes muscle atrophy, may augment subsequent release of reactive oxygen species leading to protein ubiquitination and degradation. Spinal cord injury is a unique form of disuse atrophy as there is a complete or partial disruption in tonic communication between the central nervous system (CNS) and skeletal muscle. Paralysis, unloading and disruption of CNS communication result in a rapid decline in skeletal muscle function and metabolic status with disruption in activity of peroxisome-proliferator-activated receptor-gamma co-activator 1 alpha and calcineurin, key regulators of mitochondrial health and function. External interventions, both acute and chronical with training using body-weight-assisted treadmill training or electrical stimulation have consistently demonstrated adaptations in skeletal muscle mitochondria, and expression of the genes and proteins required for mitochondrial oxidation of fats and carbohydrates to ATP, water, and carbon dioxide. The purpose of this mini-review is to highlight our current understanding as to how paralysis mechanistically triggers downstream regulation in mitochondrial density and activity and to discuss how mitochondrial dysfunction may contribute to skeletal muscle atrophy.
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PMID:Mitochondrial health and muscle plasticity after spinal cord injury. 3053 2

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