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)

Atopic dermatitis (AD) is a common disease in children. Despite good skin care and trigger avoidance, many children with AD require pharmacologic treatment to manage their disease. In recent years, topical calcineurin inhibitors (TCIs) have been used as an alternative to topical corticosteroids to treat some children with AD. However, revisions to the US labeling for TCIs (i.e. a boxed warning and a medication guide) have generated concern among pediatricians regarding TCI safety and raised questions about the appropriate use of TCIs in the pediatric population. Data from several well designed studies support the efficacy of TCIs in the treatment of AD. Safety concerns arise from a small number of reported malignancies, animal toxicology studies, and the potential adverse effects (including immunosuppression and risk of lymphoma) observed in patients who received systemically administered calcineurin inhibitors for suppression of solid-organ transplant rejection. Several factors indicate that these effects do not occur with topical administration: (i) systemic levels following topical administration are at least 10-fold lower than with oral administration; (ii) the small number of lymphomas reported to date in persons exposed to TCI use are not consistent with the types seen in transplant patients or other immunosuppressed patients; and (iii) no adverse effects on the immune system (as assessed by measures including vaccination response and skin delayed-type hypersensitivity reaction) have been observed in clinical trials of TCIs in children with AD. Overall, TCIs have an established safety and efficacy profile as long-term maintenance therapy in children with AD.
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PMID:Topical calcineurin inhibitors in pediatric atopic dermatitis: a critical analysis of current issues. 1792 1

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.
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PMID:Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies. 1802 73

The calcineurin/NFAT signaling pathway is unique to vertebrates and clear genetic evidences show that it plays critical roles in orchestrating the intricate cellular interactions that characterize vertebrate development and morphogenesis. In this setting, the transcriptional regulators of the NFAT family function as molecular integrators of specific calcium signals with other signaling pathways, including MAPkinase, WNT or NOTCH. Deregulation of calcineurin/NFAT signaling and/or abnormal expression of its components have recently been reported in solid tumors of epithelial origin, lymphoma and lymphoid leukemia. Our studies in mouse models of human T-ALL/lymphoma shows that persistent activation of calcineurin/NFAT signaling is pro-oncogenic in vivo and can be efficiently targeted by well-characterized calcineurin inhibitors. We further discuss facts and hypotheses concerning the molecular events that may act upstream and downstream of calcineurin and/or NFAT activation in different type of cancer cells.
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PMID:The calcineurin/NFAT signaling pathway: a novel therapeutic target in leukemia and solid tumors. 1823 36

In order to exert their activity, transcription factors must be transported to the nucleus. Certain transcription factors have also been found on mitochondria. Here, the localization of RelB and NFATx in the mitochondrial fractions of normal thymocytes and thymic lymphoma cells is shown for the first time. CREB was only found in the nucleus, while p50 (NFkappaB) was found in both the nucleus and the cytoplasm, but outside the mitochondria. The translocation of transcription factors to the mitochondria is differentially regulated. Unlike RelB, which is always present in the mitochondrial fraction, NFATx appeared on the mitochondria in cells treated with ionomycin together with an immunosuppressant and inhibitor of calcineurin (FK506). This data reveals that the mitochondrial localization of some transcription factors is precisely controlled by a calcium signal sensitive to FK506 in T cells.
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PMID:The mitochondrial localization of RelB and NFATx in immature T cells. 1846 95

The association between severe long-term atopic dermatitis (AD) and the risk of skin lymphoma is still a matter of debate, since epidemiological studies have shown contradictory results. We report 2 cases of patients with a documented history of severe longstanding atopic disease, who had never been treated with topical or systemic calcineurin inhibitors, and who developed a cytotoxic cutaneous T cell lymphoma (CTCL). For these 2 patients, clinical manifestations preceded the diagnosis of CTCL. The diagnosis was based on histological findings and molecular analysis of the T cell receptor (TCR) clonality. These cases illustrate the difficulty in diagnosing CTCL in patients with severe AD and extensive inflammatory skin lesions. The transition between severe AD and CTCL is progressive; histological findings and molecular evidence of TCR clonality are detected after the clinical changes. These 2 cases lend further support to the hypothesis of an association between severe long-term AD and CTCL.
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PMID:Cutaneous T cell lymphoma complicating severe atopic dermatitis. Is making a diagnosis the main challenge? 1906 Apr 56

The control of T-cell survival is of overwhelming importance for preventing leukemia and lymphoma. The present report demonstrates that the serine/threonine protein phosphatase PP4 regulates the survival of both leukemic T-cells and untransformed human peripheral blood T-cells, particularly after treatment with anti-leukemic drugs and other cytotoxic stimuli. PP4-induced apoptosis is mediated, at least in part, through de-phosphorylation of apoptosis regulator PEA-15, previously implicated in the control of leukemic cell survival. PP4 activity significantly affects the mutation rate in leukemic T-cells, indicating that PP4 dysfunction may be important in the development and progression of leukemia.
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PMID:Protein phosphatase 4 regulates apoptosis in leukemic and primary human T-cells. 1953 71

The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapamycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. Furthermore, knockdown of the mTORC2 component rictor, but not the mTORC1 component raptor, inhibited rapamycin-induced Akt phosphorylation in lymphoma cells. Addition of the histone deacetylase inhibitor (HDI) LBH589 (LBH) overcame rapamycin resistance by blocking mTOR, thus preventing Akt activation. Further studies support the involvement of the protein phosphatase PP1 in LBH-mediated Akt dephosphorylation, which could be mimicked by knockdown of HDAC3. This is the first demonstration that a HDI such as LBH can overcome rapamycin resistance through a phosphatase that antagonizes mTORC2 activation. These results provide a mechanistic rationale for a clinical trial of a combination of HDI and mTOR inhibitors for DLBCL.
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PMID:Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. 1964 Nov 86

Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by active c-Myc and PLC-beta3 deficiency was suggested in mouse lymphomas in PLC-beta3(-/-) and in Emicro-myc;PLC-beta3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor.
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PMID:Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat5. 1964 18

A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2-4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference.
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PMID:Anti-CD44 induces apoptosis in T lymphoma via mitochondrial depolarization. 1976 70

Topical calcineurin inhibitors have developed a bad connotation because of a black-box warning that was based on safety concerns of hypothetic systemic absorption and because systemic treatment with calcineurin inhibitors in patients who receive organ transplants is associated with an increased cancer risk. A few case reports of lymphoma and skin cancer in patients treated with topical calcineurin inhibitors initiated the discussion. These drugs were recommended for use as second-line therapy for the short-term and noncontinuous treatment of atopic dermatitis in patients who do not respond adequately to topical corticosteroids or in whom they are contraindicated. According to the latest knowledge, there is no scientific evidence of an increased risk for malignancy due to a topical treatment with calcineurin inhibitors.
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PMID:Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. 2008 51


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