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)

Calreticulin is a ubiquitous Ca2+ binding protein, located in the endoplasmic reticulum lumen, which has been implicated in many diverse functions including: regulation of intracellular Ca2+ homeostasis, chaperone activity, steroid-mediated gene regulation, and cell adhesion. To understand the physiological function of calreticulin we used gene targeting to create a knockout mouse for calreticulin. Mice homozygous for the calreticulin gene disruption developed omphalocele (failure of absorption of the umbilical hernia) and showed a marked decrease in ventricular wall thickness and deep intertrabecular recesses in the ventricular walls. Transgenic mice expressing a green fluorescent protein reporter gene under the control of the calreticulin promoter were used to show that the calreticulin gene is highly activated in the cardiovascular system during the early stages of cardiac development. Calreticulin protein is also highly expressed in the developing heart, but it is only a minor component of the mature heart. Bradykinin-induced Ca2+ release by the InsP3-dependent pathway was inhibited in crt-/- cells, suggesting that calreticulin plays a role in Ca2+ homeostasis. Calreticulin-deficient cells also exhibited impaired nuclear import of nuclear factor of activated T cell (NF-AT3) transcription factor indicating that calreticulin plays a role in cardiac development as a component of the Ca2+/calcineurin/NF-AT/GATA-4 transcription pathway.
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PMID:Calreticulin is essential for cardiac development. 1008 86

Calreticulin is a Ca(2+)-binding molecular chaperone of the lumen of the endoplasmic reticulum. Calreticulin has been shown to be essential for cardiac and neural development in mice, but the mechanism by which it functions in cell differentiation is not fully understood. To examine the role of calreticulin in cardiac differentiation, the calreticulin gene was introduced into rat cardiomyoblast H9c2 cells, and the effect of calreticulin overexpression on cardiac differentiation was examined. Upon culture in a differentiation medium containing fetal calf serum (1%) and retinoic acid (10 nm), cells transfected with the calreticulin gene were highly susceptible to apoptosis compared with controls. In the gene-transfected cells, protein kinase B/Akt signaling was significantly suppressed during differentiation. Furthermore, protein phosphatase 2A, a Ser/Thr protein phosphatase, was significantly up-regulated, implying suppression of Akt signaling due to dephosphorylation of Akt by the up-regulated protein phosphatase 2A via regulation of Ca(2+) homeostasis. Thus, overexpression of calreticulin promotes differentiation-dependent apoptosis in H9c2 cells by suppressing the Akt signaling pathway. These findings indicate a novel mechanism by which cytoplasmic Akt signaling is modulated to cause apoptosis by a resident protein of the endoplasmic reticulum, calreticulin.
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PMID:Overexpression of calreticulin modulates protein kinase B/Akt signaling to promote apoptosis during cardiac differentiation of cardiomyoblast H9c2 cells. 1190 32

Calreticulin is an endoplasmic reticulum resident Ca(2+)-binding chaperone. The importance of the protein is illustrated by embryonic lethality because of impaired cardiac development in calreticulin-deficient mice. The molecular details underlying this phenotype are not understood. In this study, we show that overexpression of activated calcineurin reverses the defect in cardiac development observed in calreticulin-deficient mice and rescues them from embryonic lethality. The surviving mice show no defect in cardiac development but exhibited growth retardation, hypoglycemia, increased levels of serum triacylglycerols, and cholesterol. Reversal of embryonic lethality because of calreticulin deficiency by activated calcineurin underscores the impact of the calreticulin-calcineurin functions on the Ca(2+)-dependent signaling cascade during early cardiac development. These findings show that calreticulin and calcineurin play fundamental roles in Ca(2+)-dependent pathways essential for normal cardiac development and explain the molecular basis for the rescue of calreticulin-deficient phenotype.
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PMID:Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse. 1237 73

Calreticulin is a Ca(2+) binding/storage chaperone resident in the lumen of endoplasmic reticulum (ER). The protein is an important component of the calreticulin/calnexin cycle and the quality control pathways in the ER. In mice, calreticulin deficiency is lethal due to impaired cardiac development. This is not surprising because the protein is expressed at high level at early stages of cardiac development. Overexpression of the protein in developing and postnatal heart leads to bradycardia, complete heart block and sudden death. Recent studies on calreticulin-deficient and transgenic mice revealed that the protein is a key upstream regulator of calcineurin-dependent pathways during cardiac development. Calreticulin and ER may play important role in cardiac development and postnatal pathologies.
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PMID:Calreticulin in cardiac development and pathology. 1244 56

Ca(2+) is a signalling molecule involved in virtually every aspect of cell function. The endoplasmic reticulum (ER) is an important and dynamic organelle responsible for storage of the majority of intracellular Ca(2+). Within the ER lumen are proteins that function as Ca(2+) buffers and/or molecular chaperones including calreticulin, a multifunctional Ca(2+)-binding protein. Calreticulin-deficiency is lethal in utero due to impaired cardiac development. In the absence of calreticulin Ca(2+) storage capacity in the ER and InsP(3) receptor mediated Ca(2+) release from ER are compromised. Remarkably, over-expression of constitutively active calcineurin in the hearts of calreticulin deficient mice rescues them from embryonic lethality and produces live calreticulin deficient animals. These observations provide first evidence that calreticulin is a key upstream regulator of calcineurin in the Ca(2+)-signalling cascade and they highlight the importance of ER during early stages of cellular commitment and tissue development during organogenesis.
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PMID:Calreticulin is an upstream regulator of calcineurin. 1462 3

Calcium (Ca2+) is a universal signalling molecule involved in many aspects of cellular function. The majority of intracellular Ca2+ is stored in the endoplasmic reticulum and once Ca2+ is released from the endoplasmic reticulum, specific plasma membrane Ca2+ channels are activated, resulting in increased intracellular Ca2+. In the lumen of the endoplasmic reticulum, Ca2+ is buffered by Ca2+ binding chaperones such as calreticulin. Calreticulin-deficiency is lethal in utero due to impaired cardiac development and in the absence of calreticulin, Ca2+ storage capacity within the endoplasmic reticulum and inositol 1,4,5-trisphosphate (InsP3) receptor mediated Ca2+ release from the endoplasmic reticulum are compromised. Over-expression of constitutively active calcineurin in the heart rescues calreticulin-deficient mice from embryonic lethality. This observation indicates that calreticulin is a key upstream regulator of calcineurin in Ca2+-signalling pathways and highlights the importance of the endoplasmic reticulum and endoplasmic reticulum-dependent Ca2+ homeostasis for cellular commitment and tissue development during organogenesis. Furthermore, Ca2+ handling by the endoplasmic reticulum has profound effects on cell sensitivity to apoptosis. Signalling between calreticulin in the lumen of the endoplasmic reticulum and calcineurin in the cytoplasm may play a role in the modulation of cell sensitivity to apoptosis and the regulation of Ca2+-dependent apoptotic pathways.
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PMID:Calreticulin, Ca2+, and calcineurin - signaling from the endoplasmic reticulum. 1523 10

Calreticulin is an endoplasmic reticulum-resident chaperone that is stored in the cytotoxic granules of CTLs and NK cells and is released with granzymes and perforin upon recognition of target cells. To investigate the role of calreticulin in CTL-mediated killing, we generated CTL lines from crt(+/+) and crt(-/-) mice expressing a constitutively active form of calcineurin in the heart. Crt(-/-) CTLs showed reduced cytotoxic activity toward allogeneic target cells despite normal production, intracellular localization, and activity of granzymes and despite perforin overexpression. Comparable or higher amounts of granzymes were degranulated by crt(-/-) cells in response to immobilized anti-CD3 Abs, indicating that calreticulin is dispensable for the signal transduction that leads to granule exocytosis. The ability to form conjugates with target cells was affected in the crt(-/-) CTLs, explaining the observed reduction in cytotoxicity. Conjugate formation and cytotoxicity were completely restored by treatments that facilitate recognition and contact with target cells, a prerequisite for degranulation and killing. Therefore, we conclude that calreticulin is dispensable for the cytolytic activity of granzymes and perforin, but it is required for efficient CTL-target cell interaction and for the formation of the death synapse.
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PMID:Impaired cytolytic activity in calreticulin-deficient CTLs. 1574 51

Calreticulin is a Ca(2+)-binding chaperone of the sarcoplasmic/endoplasmic reticulum. It is an important Ca(2+) buffer, a regulator of Ca(2+) homeostasis, and a component of protein quality control processes in the secretory pathway. Calreticulin is essential for cardiac development; its gene is tightly regulated during cardiogenesis, and in the absence of calreticulin, cardiac development is impaired. The protein is highly expressed in the developing heart and down-regulated after birth in the healthy mature heart. Overexpression of calreticulin in postnatal heart leads to bradyarrhythima and complete heart block, followed by sudden death. The calreticulin gene is a target of transcription factors involved in fetal cardiac program (Nkx2.5, myocardin, myocyte enhancer factor 2C, and GATA6). Calreticulin works upstream of calcineurin and myocyte enhancer factor 2C in a Ca(2+)-dependent signal transduction cascade linking the endoplasmic reticulum and the nucleus during cardiac development.
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PMID:Assembling pieces of the cardiac puzzle; calreticulin and calcium-dependent pathways in cardiac development, health, and disease. 1654 85

Radiotherapy is the primary and most important adjuvant therapy for malignant gliomas. Although the mechanism of radiation resistance in gliomas has been studied for decades, it is still not clear how the resistance is related with functions of molecular chaperones in the endoplasmic reticulum. Calreticulin (CRT) is a Ca(2+)-binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that changes in intracellular Ca(2+) homeostasis play a role in the modulation of apoptosis. In the present study, we found that the level of CRT was higher in neuroglioma H4 cells than in glioblastoma cells (U251MG and T98G), and was well correlated with the sensitivity to gamma-irradiation. To examine the role of CRT in the radiosensitivity of malignant gliomas, the CRT gene was introduced into U251MG cells, which express low levels of CRT, and the effect of overexpression of CRT on the radiosensitivity was examined. The cells transfected with the CRT gene exhibited enhanced radiation-induced apoptosis compared with untransfected control cells. In CRT-overexpressing cells, cell survival signaling via Akt was markedly suppressed. Furthermore, the gene expression of protein phosphatase 2Ac alpha (PP2Ac alpha), which is responsible for the dephosphorylation and inactivation of Akt, was up-regulated in CRT-overexpressing cells, and the regulation was dependent on Ca(2+). Thus, overexpression of CRT modulates radiation-induced apoptosis by suppressing Akt signaling through the up-regulation of PP2Ac alpha expression via altered Ca(2+) homeostasis. These results show the novel mechanism by which CRT is involved in the regulation of radiosensitivity and radiation-induced apoptosis in malignant glioma cells.
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PMID:Calreticulin, a molecular chaperone in the endoplasmic reticulum, modulates radiosensitivity of human glioblastoma U251MG cells. 1695 Nov 81

Fibroblast growth factor 2 (FGF-2) plays an integral role in therapeutic angiogenesis associated with myocardial infarct healing. Calcium (Ca(2+)) is one of the most universal important signaling molecules that affect cell proliferation and angiogenesis. Calreticulin (CRT), a 46-kd (Ca(2+)) -binding chaperone found mainly in the endoplasmic reticulum, plays an important role in regulating calcium homeostasis. The role of CRT in FGF-2-induced angiogenesis and its signaling pathways in ischemic myocardium are not clear. For this study, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization mass spectrometry were used to analyze CRT's differential expression in myocardial microvascular endothelial cells treated with or without FGF-2. Western blotting analysis was used to detect the expression of CRT and calcineurin (CaN) in sham-operated, FGF-2-, or saline intramyocardially injected myocardium. It is found that FGF-2 induced angiogenesis after sustained ischemia with downregulation of CRT expression and upregulation of CaN expression in myocardium. The CRT expression was negatively correlated to angiogenesis. Furthermore, overexpression of CRT or inhibition of CaN with cyclosporine A abolishes FGF-2-induced microvascular endothelial cells proliferation and CaN expression. The results indicate that intramyocardial administration of FGF-2 decreases myocardial CRT expression in parallel with myocardial angiogenesis in ischemic myocardium. The study further indicates that Ca(2+)/CaN signaling pathway may be involved in CRT-related angiogenesis.
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PMID:Calreticulin downregulation is associated with FGF-2-induced angiogenesis through calcineurin pathway in ischemic myocardium. 1769 30


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