Topic
Calcineurin
About: Calcineurin is a research topic. Over the lifetime, 6326 publications have been published within this topic receiving 266337 citations.
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TL;DR: The results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and Fk506 by forming drug-dependent complexes with and altering the activity of calcineURin-calmodulin.
3,968 citations
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TL;DR: It is shown that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus.
2,596 citations
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TL;DR: It is concluded that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of this pathway can oppose muscle atrophy induced by disuse.
Abstract: Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms. The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in vitro, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy. Furthermore, rapamycin, a selective blocker of mTOR, blocked hypertrophy in all models tested, without causing atrophy in control muscles. In contrast, the calcineurin pathway was not activated during hypertrophy in vivo, and inhibitors of calcineurin, cyclosporin A and FK506 did not blunt hypertrophy. Finally, genetic activation of the Akt/mTOR pathway was sufficient to cause hypertrophy and prevent atrophy in vivo, whereas genetic blockade of this pathway blocked hypertrophy in vivo. We conclude that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of the Akt/mTOR pathway can oppose muscle atrophy induced by disuse.
2,439 citations
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TL;DR: Recent findings that indicate CsA and FK506 operate as prodrugs are reviewed: they bind endogenous intracellular receptors, the immunophilins, and the resulting complex targets the protein phosphatase, calcineurin, to exert the immunosuppressive effect.
2,032 citations
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TL;DR: It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
Abstract: THE immunosuppressive drugs cyclosporin A (CsA) and FKS06 both interfere with a Ca2+-sensitive T-cell signal transduction pathway1–4thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A)1,5–7involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors8–10, cyclophilin and FKBP, respectively (see ref. 11 for review). The Ca2+/calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro12We have therefore tested the hypothesis that this interaction is responsible for the in vivo effects of CsA/FK506. We report here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription. These results identify calcineurin as a key enzyme in the T-cell signal transduction cascade and provide biological evidence to support the notion that the interaction of drug-isomerase complexes with calcineurin underlies the molecular basis of CsA/FK506-mediated immunosuppression.
1,639 citations