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)

Signal transduction pathways in megakaryocytes, a rare population of bone marrow cells, are poorly understood. We have previously shown that the calcineurin-dependent transcription factor Nuclear Factor of Activated T cells (NFAT) is expressed in megakaryocytes and is required for the transcription of specific megakaryocytic genes. The biological role of NFAT in megakaryocytes, however, is unknown. Here we show that activation of the calcineurin/NFAT pathway in megakaryocytes forces the cells to go into apoptosis. Calcineurin/NFAT activation in megakaryocytes leads to membrane expression of Fas ligand (FASLG), a pro-apoptotic member of the tumour necrosis factor superfamily. Expression of FASLG was augmented in cells stably overexpressing NFATC2 and suppressed in cells either pretreated with the calcineurin inhibitor ciclosporin A (CsA) or expressing the specific peptide inhibitor of NFAT, VIVIT. In cocultures with Fas-expressing Jurkat T cells, the presence of activated megakaryocytic cells, but not of unstimulated cells or cells stimulated in the presence of CsA, significantly induced apoptosis in Jurkat cells in a Fas/FASLG- and NFAT-dependent manner. These results represent the first evidence for a biological function of the calcineurin/NFAT pathway in megakaryocytes, and suggest that the biological role of megakaryocytes may include the induction of apoptosis in bystander cells.
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PMID:Regulation of fas/fas ligand-mediated apoptosis by nuclear factor of activated T cells in megakaryocytes. 2217 18

Klotho acts as a co-receptor for and dictates tissue specificity of circulating FGF23. FGF23 inhibits PTH secretion, and reduced Klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. To dissect the role of parathyroid gland resident Klotho in health and disease, we generated mice with a parathyroid-specific Klotho deletion (PTH-KL(-/-)). PTH-KL(-/-) mice had a normal gross phenotype and survival; normal serum PTH and calcium; unaltered expression of the PTH gene in parathyroid tissue; and preserved PTH response and sensitivity to acute changes in serum calcium. Their PTH response to intravenous FGF23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted FGF23-induced activation of the MAPK/ERK pathway. Importantly, calcineurin-NFAT signaling, defined by increased MCIP1 level and nuclear localization of NFATC2, was constitutively activated in PTH-KL(-/-) mice. Treatment with the calcineurin-inhibitor cyclosporine A abolished FGF23-mediated PTH suppression in PTH-KL(-/-) mice whereas wild-type mice remained responsive. Similar results were observed in thyro-parathyroid explants ex vivo. Collectively, we present genetic and functional evidence for a novel, Klotho-independent, calcineurin-mediated FGF23 signaling pathway in parathyroid glands that mediates suppression of PTH. The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.
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PMID:Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. 2434 62

Obesity is associated with changes in the immune system that significantly hinder its ability to mount efficient immune responses. Previous studies have reported a dysregulation of immune responses caused by lipid challenge; however, the mechanisms underlying that dysregulation are still not completely understood. Autophagy is an essential catabolic process through which cellular components are degraded by the lysosomal machinery. In T cells, autophagy is an actively regulated process necessary to sustain homeostasis and activation. Here, we report that CD4+ T cell responses are inhibited when cells are challenged with increasing concentrations of fatty acids. Furthermore, analysis of T cells from diet-induced obese mice confirms that high lipid load inhibits activation-induced responses in T cells. We have found that autophagy is inhibited in CD4+ T cells exposed in vitro or in vivo to lipid stress, which causes decreased autophagosome formation and degradation. Supporting that inhibition of autophagy caused by high lipid load is a key mechanism that accounts for the effects on T cell function of lipid stress, we found that ATG7 (autophagy-related 7)-deficient T cells, unable to activate autophagy, did not show additional inhibitory effects on their responses to activation when subjected to lipid challenge. Our results indicate, thus, that increased lipid load can dysregulate autophagy and cause defective T cell responses, and suggest that inhibition of autophagy may underlie some of the characteristic obesity-associated defects in the T cell compartment.Abbreviations: ACTB: actin, beta; ATG: autophagy-related; CDKN1B: cyclin-dependent kinase inhibitor 1B; HFD: high-fat diet; IFNG: interferon gamma; IL: interleukin; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK: mitogen-activated protein kinase 8; LC3-I: non-conjugated form of MAP1LC3B; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3B; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; NFATC2: nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2; NLRP3: NLR family, pyrin domain containing 3; OA: oleic acid; PI: propidium iodide; ROS: reactive oxygen species; STAT5A: signal transducer and activator of transcription 5A; TCR: T cell receptor; TH1: T helper cell type 1.
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PMID:The negative effect of lipid challenge on autophagy inhibits T cell responses. 3098 1