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)

Organ transplantation offers new life to patients who suffer from incurable disease. The problem of rejection of the transplanted organ has been overcome with the use of potent immunosuppressive drugs. These drugs, although they allow graft tolerance and graft survival, also are associated with complications such as osteoporosis. Although factors such as nutrition, gonadal status, and ambulatory status are important, the use of immunosuppressive drugs appears to be the main factor in the development of osteoporosis. The drugs that are responsible for this bone loss are glucocorticoids and the calcineurin phosphatase inhibitors, cyclosporine and tacrolimus. The incidence of bone disease depends, in part, on which organ is transplanted. Kidney transplant recipients appear to be less susceptible to the development of overt osteoporosis than do heart or liver transplant recipients. The most critical period of bone loss in organ recipients appears to be within the first 6 months, with the most dramatic reduction occurring within the first 3 months following transplantation. Trabecular (cancellous) bone of the spine appears to be most at risk, with vertebral fractures occurring most commonly. Transplant recipients should be evaluated by bone mineral densitometry and measurement of vitamin D metabolites, blood urea nitrogen, creatinine, calcium, and phosphate. Markers of bone turnover may help in assessing the rate of remodeling. Gonadal function should be ascertained by measurement of serum testosterone (males) or estradiol (females) levels. Therapy should be directed toward prevention of bone loss as well as helping to restore what already may have been lost. Administration of calcium and vitamin D and sex hormone replacement, if indicated, should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Organ transplantation and osteoporosis. 761 20

Although steroid hormone receptor activation has been known to be dependent on ligand binding, we report here ligand-independent transcriptional activation of the vitamin D receptor and retinoid receptors. In these studies, CV1 cells were transiently transfected with a human vitamin D receptor (VDR) expression vector and a reporter plasmid that contains multiple copies of the rat osteocalcin vitamin D response element up-stream of the bacterial chloramphenicol acetyltransferase (CAT) gene [osteocalcin (OC)VDREtkCAT]. Treatment of cells with 10(-8) M 1,25-dihydroxyvitamin D3 resulted in a 25-fold induction of CAT activity. When cells were treated with 5-50 nM okadaic acid (OA), an inhibitor of protein phosphatase-1 and -2A, significant inductions of CAT activity (18- to 57-fold) were observed. As VDR and dopamine receptors are colocalized in certain brain regions, we also examined whether VDR-mediated transcription can be activated by dopamine. VDR was found to activate CAT gene expression in cells treated with 200-500 microM dopamine (3- to 11-fold induction) or the selective D1 agonist SKF38393 (20-fold induction). Cells were also transfected with retinoic acid receptor (RAR) or retinoid-X receptor (RXR) expression vectors and reporter plasmids that contain either a retinoic acid response element or an RXR-specific response element. OA alone induced chloramphenicol acetyltransferase (CAT) activity in cells transfected with RAR alpha, RAR beta, RXR alpha, RXR beta, or RXR gamma (3- to 18-fold induction). However, OA did not affect transcription by RAR gamma, suggesting specificity of activation by OA among the retinoid receptors. Although the retinoid receptors have been detected in brain, maximum stimulation of transcription was not greater than 1.6-fold in the presence of 100-500 microM dopamine or 100 microM SKF38393 treatment. These data suggest specificity for dopamine activation among steroid hormone receptors and that phosphorylation alone, in the absence of ligand, can activate VDR- and retinoid receptor-mediated transcription.
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PMID:Ligand occupancy is not required for vitamin D receptor and retinoid receptor-mediated transcriptional activation. 777 73

Our laboratory has recently demonstrated that 1,25-dihydroxyvitamin D3(1,25(OH)2D3) rapidly stimulated membrane polyphosphoinositide breakdown and increased intracellular calcium, as well as activated protein kinase C (PKC) in vitamin D-sufficient rat colonocytes. These effects of 1,25(OH)2D3 were, however, lost in vitamin D-insufficient rats and restored by the in vivo repletion of 1,25(OH)2D3. In the present studies we have examined the ability of 1,25(OH)2D3 to stimulate the phosphorylation of colonic membrane proteins in intact D-sufficient cells. In addition, we investigated the effects of vitamin D status on the phosphorylation of these membrane proteins in broken cell preparations. These studies demonstrated that 1,25(OH)2D3 increased the phosphorylation of at least two colonic membrane proteins with apparent molecular weights of 42,000 (pp42) and 48,000 (pp48) in intact cells of vitamin D-sufficient rats. Moreover, in vitamin D-sufficient rats, treatment of colonocytes with 1,25(OH)2D3 or 12-O-tetradecanoyl phorbol 13-acetate (TPA), a known activator of PKC, significantly increased the phosphorylation of pp42 and pp48 in broken cell preparations. The kinetics of these phosphorylations in response to 1,25(OH)2D3 were both rapid and transient. In addition, PKC19-36, a specific PKC inhibitor, decreased the phosphorylation of pp42 and pp48, whereas okadaic acid (OA), a type 1 and 2A protein phosphatase inhibitor, further augmented their phosphorylation in response to 1,25(OH)2D3. The isoelectric points of pp42 and pp48 were 5.79 and 5.97, respectively, and both were predominantly phosphorylated on threonine residues. In contrast to our findings in colonocytes from vitamin D-sufficient animals, basal phosphorylation of pp42 and pp48 were increased in membranes prepared from vitamin D-insufficient rats. Moreover, these phosphorylations failed to change in response to 1,25(OH)2D3-treatment of colonocytes from vitamin D-insufficient rats. The basal phosphorylation of each of these proteins was restored to control levels, as was their ability to respond to the direct addition of 1,25(OH)2D3 following the in vivo repletion of vitamin D-insufficient rats with this secosteroid. In summary, we have identified two acidic membrane proteins from rat colonocytes that are phosphorylated in both intact and broken cell preparations in response to 1,25(OH)2D3 treatment, an event modulated by vitamin D status and mediated, at least in part, by PKC.
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PMID:1,25-Dihydroxyvitamin D3 stimulates the phosphorylation of two acidic membrane proteins of 42,000 and 48,000 daltons in rat colonocytes: an effect modulated by vitamin D status. 782 28

Within the past 2 decades, organ transplantation has become established as effective therapy for endstage renal, hepatic, cardiac, and pulmonary disease. Regimens to prevent rejection after transplantation commonly include high-dose glucocorticoids and calcineurin-calmodulin phosphatase inhibitors (the cyclosporines and tacrolimus), which are detrimental to bone and mineral homeostasis, and are associated with rapid bone loss that is often superimposed upon an already compromised skeleton. The incidence of fracture ranges from 8% to 65% during the first year after transplantation. In general, fracture rates are lowest in renal transplant recipients and highest in patients who receive a liver transplant for primary biliary cirrhosis. Rates of bone loss and fracture are greatest during the first 6 to 12 months after transplantation. Postmenopausal women and hypogonadal men appear to be at increased risk. Although no pretransplant densitometric or biochemical parameter has yet been identified that adequately predicts fracture risk in the individual patient, low pretransplant bone mineral density does tend to increase the risk of fracture, particularly in women. However, patients may sustain fractures despite normal pretransplant bone mineral density. Although the pathogenesis of the rapid bone loss is multifactorial, prospective biochemical data suggest that uncoupling of bone formation from resorption may be in part responsible, at least during the first 3 to 6 months. Prevention of transplantation osteoporosis should begin well before transplantation. Patients awaiting transplantation should be evaluated with spine radiographs, bone densitometry, thyroid function tests, serum calcium, vitamin D, parathyroid hormone, and testosterone (in men). Therapy for osteoporosis, low bone mass, and potentially reversible biochemical causes of bone loss should be instituted during the waiting period before transplantation. In patients with normal pretransplant bone density, therapy to prevent early posttransplant bone loss should be instituted immediately following transplantation. Most pharmacologic agents available for therapy of osteoporosis have not been subject to prospective controlled studies in organ transplant recipients. However, antiresorptive drugs, such as biphosphonates, appear to hold therapeutic promise.
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PMID:Osteoporosis after organ transplantation. 962 30

Successful renal transplantation is associated with abnormalities of function of the musculoskeletal system. Some of these problems result from incomplete resolution of abnormalities of mineral metabolism associated with end-stage renal disease, such as persistent hyperparathyroidism, hypercalcemia and decreased vitamin D. However, it is now appreciated that skeletal abnormalities, especially osteopenia with subsequent fractures, develop following transplantation. Most of the new disorders of bone and mineral metabolism are secondary to the immunosuppression required to prevent rejection. Glucocorticoids can not only induce osteonecrosis, but also increase the risk for fractures by decreasing cancellous bone mass and synthesis of bone matrix, and dampen the linear growth response in pediatric recipients. Other immunosuppressive agents, especially the calcineurin-phosphate inhibitors, independently exert a negative effect on bone. Future investigation is required to develop a better understanding of the pathophysiologic mechanisms involved in post-transplant bone disease in order to develop rational approaches for prevention and treatment.
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PMID:Mechanism of transplantation-associated bone loss. 1091 36

When UMR-106 osteoblastic cells, LLCPK1 kidney cells, and VDR transfected COS-7 cells were transfected with the rat 24-hydroxylase [24(OH)ase] promoter (-1,367/+74) or the mouse osteopontin (OPN) promoter (-777/+79), we found that the response to 1,25dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] could be significantly enhanced 2- to 5-fold by the protein phosphatase inhibitor, okadaic acid (OA). Enhancement of 1,25-(OH)(2)D(3)-induced transcription by OA was also observed using a synthetic reporter gene containing either the proximal 24(OH)ase vitamin D response element (VDRE) or the OPN VDRE, suggesting that the VDRE is sufficient to mediate this effect. OA also enhanced the 1,25-(OH)(2)D(3)-induced levels of 24(OH)ase and OPN mRNA in UMR osteoblastic cells. The effect of OA was not due to an up-regulation of VDR or to an increase in VDR-RXR interaction with the VDRE. To determine whether phosphorylation regulates VDR-mediated transcription by modulating interactions with protein partners, we examined the effect of phosphorylation on the protein-protein interaction between VDR and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex, using glutathione-S-transferase pull-down assays. Similar to the functional studies, OA treatment was consistently found to enhance the interaction of VDR with DRIP205 3- to 4-fold above the interaction observed in the presence of 1,25-(OH)(2)D(3) alone. In addition, studies were done with the activation function-2 defective VDR mutant, L417S, which is unable to stimulate transcription in response to 1,25-(OH)(2)D(3) or to interact with DRIP205. However, in the presence of OA, the mutant VDR was able to activate 24(OH)ase and OPN transcription and to recruit DRIP205, suggesting that OA treatment may result in a conformational change in the activation function-2 defective mutant that creates an active interaction surface with DRIP205. Taken together, these findings suggest that increased interaction between VDR and coactivators such as DRIP205 may be a major mechanism that couples extracellular signals to vitamin D action.
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PMID:Enhancement of VDR-mediated transcription by phosphorylation: correlation with increased interaction between the VDR and DRIP205, a subunit of the VDR-interacting protein coactivator complex. 1181 2

Dendritic cells, the most effective antigen-presenting cells for priming naive T cells and initiating immune responses, are also able to induce tolerance. This balance between immunity and tolerance depends on the functional stage of dendritic cells (DC). Activation of naive T cells by immature DC can induce tolerance. It is therefore of interest to summarize the effects of immunosuppressive agents on DC maturation and functions. In contrast to glucocorticosteroids, mycophenolate mofetil, and vitamin D(3) analogs, calcineurin inhibitors do not seem to inhibit DC maturation in in vitro culture systems. However, these molecules all appear to interfere with DC functions.
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PMID:Effects of immunosuppressive drugs on dendritic cells and tolerance induction. 1281 89

Immunosuppressant agents are used widely for a variety of diseases, and their usage will increase as organ transplantation becomes more frequent. One of the consequences of their administration is the occurrence of rapid bone loss with fractures. Generally, glucocorticoids (GC) are the main culprit, but calmodulin-calcineurin phosphatase inhibitors, e.g., cyclosporine and tacrolimus, seem to play a role as does the underlying disease, which necessitates treatment or organ transplantation. The mechanisms for the bone disease are multifactorial and actively being researched. The management at present is largely empirical and consists of calcium, vitamin D, and antiresorbers, especially bisphosphonates. In order to achieve an optimum treatment strategy, bone density measurements are essential to define the severity of the bone loss, help decide therapy and monitor progress of the patient.
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PMID:Immunosuppressant drugs and bone disease: a clinician's perspective. 1530 78

The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin Abeta gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1alpha-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.
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PMID:Calcineurin Abeta is central to the expression of the renal type II Na/Pi co-transporter gene and to the regulation of renal phosphate transport. 1557 99

Skeletal muscle is a highly adaptable tissue. It responds to environmental and physiological challenges by changes in size, fibre type and metabolism. All of these responses are underpinned by our genes and it is therefore generally assumed that genetic variation between individuals may account for the differences in musculature and athletic capabilities between people. Research into the genetic influences of our muscle is at an embryonic stage, but some early insight into potential regulators has recently emerged, which is reflected in this review. Broad heritability, which appears to affect muscle size and strength more than metabolism has been assessed in twin and sibling studies. It appears to account for more inter-individual variation in the young as opposed to older people. However, the studies reported to date do demonstrate a large degree of diversity, which is probably predominantly due to different methodological approaches being adopted as well as distinct populations being studied. At a molecular level, there has been enormous progress in identifying regulators of atrophy and hypertrophy though the study of knock-out and transgenic animals and also through the utilisation of cell culture models. Among others, the insulin-like growth factors, calcineurin, desmin, myf5, mrf4, MyoD and myogenin have been identified as positive regulators of muscle size, while TNF-alpha, myostatin and components of the ubiquitin pathway have been recognized as regulators of muscle wasting. However, given the ethical and mechanistic constraints of performing similar studies in humans, difficulties have arisen when attempting to translate the animal and cell culture findings to humans. However, the current search for target "exercise genes" in humans has yielded the first successful results. Variations in the genes encoding for: the angiotensin converting enzyme, alpha-actinin 3, bradykinin, ciliary neurotrophic factor, interleukin-15, insulin-like growth factor II, myostatin and the vitamin D-receptor have all been found to account for some of the inter-subject variability in muscle strength or size. However, the influences of these genetic variations are somewhat weak, and not always reproducible and furthermore they are predominantly based in young healthy people. Hence, a key topic, namely the molecular mechanisms of muscle frailty in the elderly still remains to be elucidated.
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PMID:Adaptive processes in skeletal muscle: molecular regulators and genetic influences. 1667 91


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