Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of Escherichia coli with phage lambda gt10 resulted in the appearance of a protein phosphatase with activity towards 32P-labelled casein. Activity reached a maximum near the point of cell lysis and declined thereafter. The phosphatase was stimulated 30-fold by Mn2+, while Mg2+ and Ca2+ were much less effective. Activity was unaffected by inhibitors 1 and 2, okadaic acid, calmodulin and trifluoperazine, distinguishing it from the major serine/threonine-specific protein phosphatases of eukaryotic cells. The lambda phosphatase was also capable of dephosphorylating other substrates in the presence of Mn2+, although activity towards 32P-labelled phosphorylase was 10-fold lower, and activity towards phosphorylase kinase and glycogen synthase 25 50-fold lower than with casein. No casein phosphatase activity was present in either uninfected cells, or in E. coli infected with phage lambda gt11. Since lambda gt11 lacks part of the open reading frame (orf) 221, previously shown to encode a protein with sequence similarity to protein phosphatase-1 and protein phosphatase-2A of mammalian cells [Cohen, Collins, Coulson, Berndt & da Cruz e Silva (1988) Gene 69, 131-134], the results indicate that ORF221 is the protein phosphatase detected in cells infected with lambda gt10. Comparison of the sequence of ORF221 with other mammalian protein phosphatases defines three highly conserved regions which are likely to be essential for function. The first of these is deleted in lambda gt11.
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PMID:Discovery of a protein phosphatase activity encoded in the genome of bacteriophage lambda. Probable identity with open reading frame 221. 254 89

Recent studies have suggested that signaling initiated by the activation of Ag receptors and signaling activated through cytokine receptors may be regulated by a common set of inhibitory proteins. Suppressor of cytokine signaling 3 (SOCS-3), which has previously been demonstrated to inhibit cytokine signaling, is induced on TCR ligation. Overexpression of SOCS-3 can inhibit transcription driven by the IL-2 promoter in response to T cell activation. This inhibitory activity correlates with the suppression of calcineurin-dependent dephosphorylation and activation of the IL-2 promoter binding transcription factor, NFATp. Infection of primary murine T cells with a retrovirus encoding SOCS-3 blocks their IL-2 production in response to activation. Interestingly, SOCS-3 was found to coimmunoprecipitate with the catalytic subunit of calcineurin. These studies suggest that SOCS-3 may regulate T cell function as part of a negative feedback loop.
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PMID:Cutting edge: Suppressor of cytokine signaling 3 inhibits activation of NFATp. 1197 Sep 67

Introduction of the constitutively active calcineurin gene into neonatal rat cardiomyocytes by adenovirus resulted in decreased mitochondrial membrane potential (P < 0.05). Infection of H9c2 cells with calcineurin adenovirus resulted in increased superoxide production (P < 0.001). Transgenic mice with cardiac-specific expression of a constitutively active calcineurin cDNA (CalTG mice) exhibit a two- to threefold increase in heart size that progresses to heart failure. We prepared mitochondria enriched for the subsarcolemmal population from the hearts of CalTG mice and transgene negative littermates (control). Intact, well-coupled mitochondria prepared from one to two mouse hearts at a time yielded sufficient material for functional studies. Mitochondrial oxygen consumption was measured with a Clark-type oxygen electrode with substrates for mitochondrial complex II (succinate) and complex IV [tetramethylpentadecane (TMPD)/ascorbate]. CalTG mice exhibited a maximal rate of electron transfer in heart mitochondria that was reduced by approximately 50% (P < 0.002) without a loss of respiratory control. Mitochondrial respiration was unaffected in tropomodulin-overexpressing transgenic mice, another model of cardiomyopathy. Western blotting for mitochondrial electron transfer subunits from mitochondria of CalTG mice revealed a 20-30% reduction in subunit 3 of complex I (ND3) and subunits I and IV of cytochrome oxidase (CO-I, CO-IV) when normalized to total mitochondrial protein or to the adenine nucleotide transporter (ANT) and compared with littermate controls (P < 0.002). Impaired mitochondrial electron transport was associated with high levels of superoxide production in the CalTG mice. Taken together, these data indicate that calcineurin signaling affects mitochondrial energetics and superoxide production. The excessive production of superoxide may contribute to the development of cardiac failure.
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PMID:Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. 1239 29

Invasive fungal infections are rising worldwide as the number of immunocompromised patients increases. Unfortunately, our armamentarium of antifungal drugs is limited. Although current therapies are effective in treating some of the most prevalent infections, the development of novel treatments is vital because of emerging drug-resistant strains and species and because of the toxicity of certain current therapies. The immunosuppressive drugs CsA (cyclosporin A), FK-506 (tacrolimus) and rapamycin (sirolimus) exert potent antifungal effects against a variety of pathogenic fungi. These compounds are all currently in clinical use as immunosuppressive therapy to treat and prevent rejection of transplanted organs. Rapamycin is also in clinical trials as an antiproliferative agent for chemotherapy and invasive cardiology. Recent studies reveal a potent fungicidal synergism between azoles and the calcineurin inhibitors CsA and FK-506, and animal studies demonstrate that the CsA-fluconazole synergistic combination has therapeutic benefit. Less immunosuppressive analogs have been identified with potential to enhance current therapies, or as monotherapy without deleterious effects on the immune system. In summary, these highly successful pharmaceutical agents may find an even broader clinical application in combating infectious diseases.
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PMID:Teaching old drugs new tricks: reincarnating immunosuppressants as antifungal drugs. 1266 81

We reviewed 43 adult kidney transplant patients (32 males and 11 females, 14-68 years of age) performed at our center between July 1999 and February 2002. Donors (39 males and 4 females) comprised two cadaverics, five living-related and 36 living-unrelated; age 18-44 years. Indications for kidney transplantation (KT) were: chronic glomerulonephritis (8), re-transplantation (4) and chronic pyelonephritis (3); kidney disease was unknown in 15 cases. ATG-F was given as a single intra-operative bolus induction therapy in 26 patients; extended ATG-F dose was given in 17 patients because of a high sensitization status, slow graft function (SGF) or development of calcineurin inhibitors toxicity. ATG-F was stopped in seven out of 17 patients because of thrombocytopenia or severe anemia. ATG-F-related fever occurred in six patients. Acute rejection (AR) occurred in eight patients (18%) 5-11 days post-KT. ATG-F was given in three steroid-resistant AR. Infection occurred in 19 patients (44%) for a total of 32 infectious episodes comprising 24 bacterial infections (nine urinary, seven catheter-related and three respiratory), six viral infections (five CMV and one herpes) and two fungal infections (one pulmonary aspergillosis and one catheter-related candidiasis). The hospital stay was 8-75 days for a median of 13 days. The mean serum creatinine upon discharge, at 1 and 6 months after KT were: 2.04+/-0.37, 1.43+/-0.16 and 1.29+/-0.08, respectively. One patient lost his graft on day 9 because of graft microthrombi related to Factor V-Leiden mutation. The 6 months actuarial patient and graft survival were 100 and 97.6%, respectively. ATG-F as a bolus therapy is an effective and safe induction treatment in KT.
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PMID:Intraoperative anti-thymocyte globulin-Fresenius (ATG-F) administration as induction immunosuppressive therapy in kidney transplantation. 1283 82

During differentiation, expression of protein phosphatase-2Calpha (PP2Calpha) is increased in 3T3-L1 adipocytes. To elucidate the role of PP2Calpha in insulin signaling, we overexpressed wild-type (WT) PP2Calpha by adenovirus-mediated gene transfer in 3T3-L1 adipocytes. Overexpression of PP2Calpha-WT enhanced the insulin sensitivity of glucose uptake without any changes in the early steps of insulin signaling. Infection with adenovirus 5 expressing PP2Calpha-WT increased phosphatidylinositol 3-kinase (PI3K) activities in the immunoprecipitate using antibody against the p85 or p110 subunit under both basal and insulin-stimulated conditions, followed by activation of downstream steps in the PI3K pathway, such as phosphorylation of Akt, glycogen synthase kinase-3, and atypical protein kinase C. In contrast, overexpression of the phosphatase-defective mutant PP2Calpha(R174G) did not produce such effects. Furthermore, overexpression of PP2Calpha-WT (but not PP2Calpha(R174G)) decreased the (32)P-labeled phosphorylation state as well as the gel mobility shift of the p85 subunit, suggesting that dephosphorylation of the p85 subunit by PP2Calpha activation might stimulate PI3K catalytic activity. Moreover, knockdown of PP2Calpha by transfection of small interfering RNA led to a significant decrease in Akt phosphorylation. In addition, microinjection of anti-PP2Calpha antibody or PP2Calpha small interfering RNA led to decreased insulin-stimulated GLUT4 translocation. In conclusion, PP2Calpha is a new positive regulator of insulin sensitivity that acts through a direct activation of PI3K in 3T3-L1 adipocytes.
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PMID:Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. 1501 18

While bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with the use of sirolimus (SIR), the incidence in a consecutive group of patients given SIR to replace a calcineurin-inhibitor (CI) is unknown. Twenty-nine consecutive cardiac transplant recipients were switched from a CI to SIR to ameliorate CI-associated nephropathy or coronary graft atherosclerosis. Seven patients (24%) developed BOOP. The clinical characteristics and biopsy results of these patients are presented. The clinical course and response to withdrawal of SIR in all and steroids in four of seven patients suggested the diagnosis of BOOP. Chest X-rays and CT scans showed typical findings of BOOP in all seven patients. Infection was excluded in all patients. Biopsy results were characteristic of BOOP in six of seven patients. Six patients recovered and one died. BOOP is a common and potentially serious adverse event in cardiac transplant patients switched from a CI to SIR, especially when SIR is started late post-transplantation.
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PMID:BOOP is common in cardiac transplant recipients switched from a calcineurin inhibitor to sirolimus. 1588 46

The time to failure of a renal allograft is determined by the initial function achieved after transplantation, the number and severity of insults to the graft, and a number of tissue characteristics. The insults a graft usually encounters include ischaemia/reperfusion injury, acute rejection episodes, drug-related nephrotoxicity, hypertension and hyperlipidaemia. Important tissue characteristics include susceptibility to injury and the ability of the tissue to repair damage. Elderly transplant recipients are considered poor immune responders but if a single acute rejection episode occurs this is more likely to significantly shorten graft and patient survival in this age group. Two issues have been identified with the use of old (>50 years of age) donor kidneys. First, compared with kidneys from younger donors, they have an increased incidence of acute interstitial rejection. Secondly, once a rejection episode occurs, the ability to mount a tissue repair process seems impaired. An explanation for the increased loss of grafts from old donors that have experienced acute rejection episodes is that such kidneys have fewer nephrons that function adequately and that the cumulated effect of damage results in an earlier demise of the graft compared with younger donor kidneys. Alternatively, graft parenchymal cells may undergo premature senescence or aging as a result of multiple injuries and repair. If progressive loss of renal mass or senescence is the mechanism responsible for increased graft loss, then it is expected that grafts from older donors will show a progressive decrease in function over time and that the rate of decline of function will correlate with donor age. We have suggested that increased graft loss of older donor kidneys results from increased incidence of acute rejection episodes in the early post-transplantation months together with a partly impaired ability to repair the tissue. Drug pharmacokinetic parameters are generally little influenced by age. However, the degree to which drugs suppress the immune system, and the extent to which kidneys from older donors are susceptible to the nephrotoxic effects of certain drugs, are unpredictable. There appears to be a more delicate balance between adequate immunosuppression and excess nonimmune toxicity in patients receiving older kidneys. Outcome parameters in elderly renal transplant recipients are currently dominated by increased death from infectious disease and drug-related (cardiovascular) causes. Increased susceptibility to nephrotoxic drugs, and to calcineurin inhibitors in particular, may be related to the increased risk of allograft failure experienced by the elderly as a surrogate for chronic allograft nephropathy.
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PMID:The impact of age on rejection in kidney transplantation. 1590 55

The major causes of renal transplant loss are death from vascular, malignant or infectious disease, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Chronic allograft nephropathy (CAN) is the histologic description of the fibrosis, vascular and glomerular damage occurring in renal allografts. Clinical programs rely on monitoring change in serum creatinine for identification of patients at risk of CAN, but this change occurs late in the course of the disease, and underestimates the severity of pathologic change. CAN has several causes: ischemia-reperfusion injury, ineffectively or untreated clinical and subclinical rejection, and superimposed calcineurin inhibitor nephrotoxicity, exacerbating pre-existing donor disease. Once established, interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerulosclerosis over the subsequent years. There have been a number of approaches to treatment aimed at reducing the impact of CAN, mostly centered around avoidance of calcineurin inhibitors through their elimination in all, or just selected, patients. These immunosuppression strategies combine corticosteroids with azathioprine or mycophenolate mofetil, and/or sirolimus and everolimus. Late identification of CAN in individual patients has meant that strategies for intervening to prevent chronic renal allograft dysfunction and subsequent graft loss tend to be "too little and far too late."
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PMID:Chronic renal allograft dysfunction. 1612 Aug 19

Overexpression of the protein phosphatase 1 (PP1) subunit protein targeting to glycogen (PTG) markedly enhances cellular glycogen levels. In order to disrupt the endogenous PTG-PP1 complex, small interfering RNA (siRNA) constructs against PTG were identified. Infection of 3T3-L1 adipocytes with PTG siRNA adenovirus decreased PTG mRNA and protein levels by >90%. In parallel, PTG reduction resulted in a >85% decrease in glycogen levels 4 days after infection, supporting a critical role for PTG in glycogen metabolism. Total PP1, glycogen synthase, and GLUT4 levels, as well as insulin-stimulated signaling cascades, were unaffected. However, PTG knockdown reduced glycogen-targeted PP1 protein levels, corresponding to decreased cellular glycogen synthase- and phosphorylase-directed PP1 activity. Interestingly, GLUT1 levels and acute insulin-stimulated glycogen synthesis rates were increased two- to threefold, and glycogen synthase activation in the presence of extracellular glucose was maintained. In contrast, glycogenolysis rates were markedly increased, suggesting that PTG primarily acts to suppress glycogen breakdown. Cumulatively, these data indicate that disruption of PTG expression resulted in the uncoupling of PP1 activity from glycogen metabolizing enzymes, the enhancement of glycogenolysis, and a dramatic decrease in cellular glycogen levels. Further, they suggest that reduction of glycogen stores induced cellular compensation by several mechanisms, but ultimately these changes could not overcome the loss of PTG expression.
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PMID:Central role for protein targeting to glycogen in the maintenance of cellular glycogen stores in 3T3-L1 adipocytes. 1635 3


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