The Mechanism of Action of FK‐506 and Cyclosporin A

Wiederrecht, Gregory; Lam, Elsa; Hung, Shirley H.Y.; Martin, Mary M.; Sigal, Nolan H.

doi:10.1111/j.1749-6632.1993.tb17137.x

Cited by 297 publications

(122 citation statements)

References 73 publications

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“…In order to confirm this, we analyzed the level of ␤-galactosidase activity in YEpTdCRZ1 transformants of the crz1⌬ strain treated with both Ca 2ϩ and the drug FK506. The immunosuppressant FK506 is a potent inhibitor of calcineurin (6,65) and has been used extensively for molecular studies in lower and higher eukaryotes (18,29,45). As shown in Table 3, addition of FK506 at 1 g/ml decreased the Ca 2ϩ -stimulated induction of ␤-galactosidase activity observed in the absence of the immunosuppressant, whereas at doses of 5 g/ml, induction was eliminated altogether ( Table 3).…”

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confidence: 92%

Regulation of Salt Tolerance byTorulaspora delbrueckiiCalcineurin Target Crz1p

et al. 2006

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Recently, the academic interest in the yeast Torulaspora delbrueckii has increased notably due to its high resistance to several types of stress, including salt and osmotic imbalance. However, the molecular mechanisms underlying these unusual properties are poorly understood. In Saccharomyces cerevisiae, the high-salt response is mediated by calcineurin, a conserved Ca 2؉ /calmodulin-modulated protein phosphatase that regulates the transcriptional factor Crz1p. Here, we cloned the T. delbrueckii TdCRZ1 gene, which encodes a putative zinc finger transcription factor homologue to Crz1p. Consistent with this, overexpression of TdCRZ1 enhanced the salt tolerance of S. cerevisiae wild-type cells and suppressed the sensitivity phenotype of cnb1⌬ and crz1⌬ mutants to monovalent and divalent cations. However, T. delbrueckii cells lacking TdCrz1p showed phenotypes distinct from those previously observed in S. cerevisiae crz1⌬ mutants. Quite remarkably, Tdcrz1-null cells were insensitive to high Na ؉ and were more Li ؉ tolerant than wild-type cells. Clearly, TdCrz1p was not required for the salt-induced transcriptional activation of the TdENA1 gene, encoding a putative P-type ATPase homologue to the main S. cerevisiae Na ؉ pump ENA1. Furthermore, T. delbrueckii cells were insensitive to the immunosuppressive agents FK506 and cyclosporine A, both in the presence and in the absence of NaCl. Signaling through the calcineurin/Crz1 pathway appeared to be essential only on high-Ca 2؉ /Mn 2؉ media. Hence, T. delbrueckii and S. cerevisiae differ in the regulatory circuits and mechanisms that drive the adaptive response to salt stress.

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confidence: 92%

Regulation of Salt Tolerance byTorulaspora delbrueckiiCalcineurin Target Crz1p

et al. 2006

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“…The complex also inhibits the activation of the transcription factor nuclear factor-ATc, thus preventing its entry into the nucleus. Consequently, the transcription of cytokines such as IL-2 and IL-4 is blocked, resulting in suppression of RA disease [12][13][14][15] . We reported previously that cyclosporine, a calcineurin inhibitor, also inhibits P-glycoprotein, and it can thus eliminate drug resistance in systemic lupus erythematosus, which is caused by drug exclusion due to expression of P-glycoprotein 9,16 .…”

Section: Rheumatologymentioning

confidence: 99%

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

et al. 2010

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ABSTRACT. Objective. Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. Methods. One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio).Results. The disease activity of enrolled patients was 5.8 ± 1.2 (mean ± SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. Conclusion. Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment. (First Release Jan 15 2010;

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“…Ciclosporin A (CsA) binds to calcineurin, an enzyme involved in signal transduction of T-lymphocytes and expression of the proinflammatory IL-2 [89]. Tacrolimus is another calcineurin inhibitor that is currently used for the prevention of transplant rejection.…”

Section: Calcineurin Inhibitorsmentioning

confidence: 99%