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)

Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases characterized by abnormal lymphoid proliferation following transplantation. These lymphomas, in particular, have been shown to have a higher incidence in renal transplant recipients compared with the general age-matched population. The effect of different immunosuppressive regimens on the incidence of PTLD has been assessed in a number of studies. Although there are conflicting data on the role of calcineurin inhibitors (CNIs) in promoting the development of PTLD, an increase in risk is described in most studies and is usually related to the aggressiveness of immunosuppression. The proliferation signal inhibitors (PSIs), everolimus and sirolimus, have both immunosuppressive and antiproliferative actions and pre-clinical data suggest that everolimus has an inhibitory effect on the growth of PTLD-derived cell lines. There is currently limited clinical data on the use of PSIs in the management of PTLD, therefore, clinical experience from nine European Transplant centres has been pooled and analysed to assess their potential. Conversion to PSIs and subsequent minimization or withdrawal of CNIs was analysed in 19 renal transplant recipients with PTLD and remission was observed in 15 patients. These data suggest that PSIs may assist with the management of PTLD following renal transplantation.
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PMID:Post-transplant lymphoproliferative disorder--the potential of proliferation signal inhibitors. 1828 44

Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre-T-cell receptor (TCR) signaling, TCR-mediated positive selection of thymocytes into mature T cells, and many aspects of the immune response. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as cyclosporin A (CsA) and FK506, are powerful immunosuppressants in wide clinical use. We observed sustained calcineurin activation in human B- and T-cell lymphomas and in all mouse models of lymphoid malignancies analyzed. In intracellular NOTCH1 (ICN1)- and TEL-JAK2-induced T-cell lymphoblastic leukemia, two mouse models relevant to human malignancies, in vivo inhibition of calcineurin activity by CsA or FK506 induced apoptosis of leukemic cells and rapid tumor clearance, and substantially prolonged mouse survival. In contrast, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression. Moreover, CsA treatment induced apoptosis in human lymphoma and leukemia cell lines. Thus, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a relevant therapeutic target in lymphoid malignancies.
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PMID:Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. 1755 30

B-lymphoid tumor cells are often less sensitive than their normal counterparts or insensitive to transforming growth factor beta1 (TGFb) effects. We studied the apoptotic effect of exogenous TGFb in B-lymphoma cells, focusing on the activity and the role of Smad and protein phosphatase/kinase signals. Recombinant TGFb treatment and Smad4 siRNA transfection were used in HT58 B-NHL lymphoma cells in vitro. Gene expression and apoptosis were detected by RT-PCR, Western blot analysis and flow cytometry. The role of MEK1 kinase and PP2A activity--measured with a phosphatase assay--were assessed with the help of specific inhibitors. Smad4 siRNA treatment completely abolished TGFb-induced early gene upregulation, indicating the absence of the rapid activation of Smad signaling. Moreover, functional inhibition of Smad4 had no influence on TGFb-induced apoptosis, but it was dependent on PP2A phosphatase activation, ERK1/2 and JNK inactivation in lymphoma cells. The results prove that exogenous TGFb uses Smad4-independent, alternative (PP2A/PP2A-like dependent) signaling pathways for apoptosis induction in lymphoma cells. Further studies are needed to clarify the possible role and involvement of Smad4-independent effects of TGFb in normal and malignant lymphoid cells and in cells of the tumor microenvironment.
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PMID:Smad4-independent, PP2A-dependent apoptotic effect of exogenous transforming growth factor beta 1 in lymphoma cells. 1764 25

Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven [including p210/p190(BCR/ABL)(T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.
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PMID:FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. 1771 97

Akt is a protein serine/threonine kinase that is involved in the regulation of diverse cellular processes. Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells. Akt was shown to associate with ectopically expressed B55alpha subunit in NIH3T3 cells. The direct interaction between B55alpha subunit and Akt was confirmed using in vitro pulldown analyses. Intriguingly, we found that overexpression of B55alpha subunit significantly impaired phosphorylation at Thr-308, but to a lesser extent at Ser-473 of Akt in both FL5.12 and NIH3T3 cells. Concomitantly, phosphorylation of a subset of Akt substrates, including FoxO3a, was substantially decreased by B55alpha overexpression in these cells. Silencing of B55alpha expression markedly increased phosphorylation at Thr-308 but not at Ser-473 in both FL5.12 cells and NIH3T3 cells. Consistently, PP2A AB55alphaC holoenzymes preferentially dephosphorylated phospho-Thr-308 rather than phospho-Ser-473 in in vitro dephosphorylation assays. Furthermore, B55alpha overexpression retarded proliferation of NIH3T3 cells, and knockdown of B55alpha expression increased survival of FL5.12 cells upon interleukin-3 deprivation. Together, our data demonstrate that B55alpha-dependent targeting of the PP2A holoenzyme to Akt selectively regulates Akt phosphorylation at Thr-308 to regulate cell proliferation and survival.
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PMID:Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. 1804 41

The ability of glucocorticoids (GCs) to kill lymphoid cells via a process called apoptosis has led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies. Since GC receptor(GR) is a ligand-dependent transcription factor, there should be genes mediating apoptosis among the ones whose expression is induced by GC. This review summarizes recent advances related to the molecular basis of GC-induced apoptosis, focusing on microarray analysis. Various groups of genes have been identified as candidate target genes of GR including the ones encoding Bcl-2 family proteins and calcineurin inhibitors. Although further investigation is required to determine the genes causally involved in GC-induced apoptosis, the studies described here will hopefully lead to more efficient treatments of lymphoid malignancies.
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PMID:[Anti-tumor activities of steroids--lessons from microarray analysis]. 1818 54

PPM1D is a PPM1 type protein phosphatase and is induced in response to DNA damage. PPM1D-deficient mice show defects in spermatogenesis and lymphoid cell functions but the mechanisms underlying these phenotypes remain unknown. In our current study, we identify and characterize an alternative splicing variant (denoted PPM1D430) of human PPM1D at both the mRNA and protein level. PPM1D430 comprises the common 420 residues of the known PPM1D protein (PPM1D605) and contains a stretch of PPM1D430-specific 10 amino acids. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that PPM1D430 mRNA is also induced in response to the genotoxic stress in a p53-dependent manner. In vitro phosphatase analysis and PPM1D430-specific RNA interference analysis further indicated that PPM1D430 can dephosphorylate Ser15 of human p53 both in vitro and in vivo. On the other hand, expression profiling of this gene by RT-PCR analysis of a human tissue cDNA panel revealed that PPM1D430 is expressed exclusively in testes and in leucocytes whereas PPM1D605 is ubiquitous. In addition, PPM1D430 shows a different subcellular localization pattern and protein stability when compared with PPM1D605 under some conditions. Our current findings thus suggest that PPM1D430 may exert specific functions in immune response and/or spermatogenesis.
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PMID:PPM1D430, a novel alternative splicing variant of the human PPM1D, can dephosphorylate p53 and exhibits specific tissue expression. 1884 66

Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the alpha isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnAalpha(+/-)) mice. In addition to renal dysfunction and inflammation, we find that CnAalpha(+/-) mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-beta is significantly increased in CnAalpha(+/-) mice. Neutralization of TGF-beta attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnAalpha causes uregulation of TGF-beta which contributes to chronic inflammation and formation of TLOs. While the process that leads to TLOs formation in transplant allografts is unknown, TLOs are associated with poor clinical prognosis. This study suggests that calcineurin inhibition itself may lead to TLO formation and that TGF-beta may be a novel therapeutic target.
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PMID:TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha heterozygous mice. 1912 56

The gut associated lymphoid tissue (GALT) is anatomical and functionally divided in inductive and effectors sites. In previous works we demonstrated that non-pathogenic bacteria with probiotic characteristics can improve the gut mucosal immune system, with an increase in the number of IgA and cytokines producing cells in the effector site of the intestine. In the present work we studied the effect of non-pathogenic Gram(+), Gram(-) bacteria and a Gram(+) probiotic strain on the inductor site (PP) after the oral administration to BALB/c mice. We also studied some signals induced by the assayed strain in the effectors site, such as the enzyme calcineurin and TLR-9 as a way to understand the mechanisms induced in such bacterial stimulation. The implicance of the lipoteichoic acid (LTA) in the immunostimulation was analyzed. All strains increased the number of IFN-gamma and TNF-alpha(+) cells, but not of IL-10(+) cells in the total population of PP. The release of IFN-gamma and TNF-alpha was only induced by LPS stimulation. All assayed strains increased the number of calcineurin(+) cells, while only Gram(+) strains increased the number of TLR-9(+) cells. The immunostimulatory properties of the purified LTA from Gram(+) strains was evaluated on a monocyte-macrophage U937 cell line. These cells showed capacity to release TNF-alpha and IL-10 in response to all LTA assayed in a dose-dependent way. Gram(+) strains induced signals through the calcineurin enzyme able to activate the transcriptional factor NFAT and through TLR-9. The LTA molecule from Gram(+) strains would not be the only structure involved in the immunostimulatory properties observed, specially for the probiotic strain.
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PMID:Immune response of non-pathogenic gram(+) and gram(-) bacteria in inductive sites of the intestinal mucosa study of the pathway of signaling involved. 1925 Jul 3

Non-Hodgkin lymphoma (NHL) incidence is greatly increased after kidney transplantation. NHL risk was investigated in a nationwide cohort of 8164 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry. NHL diagnoses were ascertained using linkage with national cancer registry records. Multivariate Poisson regression was used to compute incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing risk by transplant function, and risk factors for early (< 2 years) and late (>/= 2 years) NHL during the first transplantation. NHL occurred in 133 patients. Incidence was strikingly lower after transplant failure and cessation of immunosuppression than during transplant function (IRR, 0.25; 95% CI, 0.08-0.80; P = .019). Early NHL (n = 27) was associated with Epstein-Barr virus (EBV) seronegativity at transplantation (IRR, 4.66; 95% CI, 2.10-10.36, P < .001) and receipt of T cell-depleting antibodies (IRR, 2.39; 95% CI, 1.08-5.30; P = .031). Late NHL (n = 79) was associated with increasing year of age (IRR, 1.02; 95% CI, 1.01-1.04; P = .006), increasing time since transplantation (P < .001), and current use of calcineurin inhibitors (IRR, 3.13; 95% CI, 1.53-6.39; P = .002). These findings support 2 mechanisms of lymphomagenesis, one predominantly of primary EBV infection in the context of intense immunosuppression, and another of dysregulated lymphoid proliferation in a prolonged immunosuppressed state.
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PMID:Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. 1944 60


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