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)

The phosphatase inhibitors okadaic acid and calyculin A were used to examine the role of phosphorylation processes in T cell apoptosis induced by interleukin-2 (IL-2) deprivation or transforming growth factor-beta 2 (TGF-beta 2). Okadaic acid and calyculin A inhibited IL-2-driven T cell proliferation and induced apoptosis at concentrations known to inhibit protein phosphatase 1. High concentrations of both agents caused toxic changes of prominent cellular swelling and dilatation of rough endoplasmic reticular profiles. When the T cells were induced to undergo apoptosis by IL-2 deprivation, okadaic acid and calyculin A delayed loss of membrane integrity, nucleosomal size DNA fragmentation, and loss of bcl-2 mRNA. However, T cells deprived of IL-2 in the presence of okadaic acid or calyculin A revealed DNA breaks by in situ DNA end labeling and apoptotic morphology by electron microscopy and failed to show enhanced survival after reexposure to IL-2. Although TGF-beta-mediated signaling is thought to involve the dephosphorylation of specific substrates, okadaic acid and calyculin A not only failed to inhibit, but actually augmented, TGF-beta 2-induced inhibition of T cell proliferation and induction of apoptosis. Exposure to either TGF-beta 2 or the phosphatase inhibitors prevented phosphorylation of the retinoblastoma protein RB. In summary, okadaic acid and calyculin A: (i) induce T cell apoptosis in the presence of IL-2, (ii) allow us to distinguish essential from epiphenomenal features of T cell apoptosis after IL-2 deprivation, and (iii) cooperate with TGF-beta 2 in inducing growth arrest and apoptosis of murine T cells via intracellular cascades that converge in the prevention of RB phosphorylation.
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PMID:T cell apoptosis induced by interleukin-2 deprivation or transforming growth factor-beta 2: modulation by the phosphatase inhibitors okadaic acid and calyculin A. 749 39

Group I and Epstein-Barr virus-negative Burkitt's lymphoma cell lines and the B104 lymphoma cell line which expresses a phenotype of immature B cells undergo apoptosis after cross-linking of their surface Ig receptors or after exposure to a calcium ionophore. We show here that tumor necrosis factor (TNF)-alpha protects these B cell lines against Ca(2+)-dependent apoptosis. Protection was associated with up-regulation of bcl-2 mRNA and protein expression. The increase of Bcl-2 expression induced by TNF-alpha was inhibited by chelerythrine, a specific inhibitor of protein kinase C (PKC), suggesting that Bcl-2 expression was dependent on PKC activation. Furthermore, we show that phorbol esters and cyclosporin A (CsA), which prevent Ca(2+)-dependent apoptosis, up-regulated Bcl-2 expression. The effect of CsA on Bcl-2 expression is controlled by calcineurin since we have shown that FK506 but not rapamycin had the same effect on Bcl-2 expression, whereas okadaic acid, an inhibitor of phosphatases 1, 2A and 2C, was ineffective. These data provide direct evidence that TNF-alpha prevents Ca(2+)-dependent apoptosis by a Bcl-2-dependent mechanism mediated by PKC.
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PMID:Tumor necrosis factor-alpha up-regulates Bcl-2 expression and decreases calcium-dependent apoptosis in human B cell lines. 754 79

Mouse malignant T-lymphoma CS-21 cells grow in vitro in the presence of CA-12 stromal cells, but they undergo apoptotic cell death with DNA fragmentation when cultured alone. Because apoptosis of CS-21 cells was not inhibited by soluble factors secreted from CA-12 stromal cells, cell-cell interactions between the two seemed to be important to inhibit apoptosis. We found that CS-21 cell adhesion was mediated by M(r) 168,000 and M(r) 23,000 proteins and that apoptosis-inhibitory signals were transmitted through these proteins. In this study, we identified the M(r) 23,000 cell adhesion molecule as a glycosylphosphatidylinositol-anchored Thy-1 (CD90) glycoprotein. Cross-linking of M(r) 23,000 protein with anti-M(r) 23,000 mAb and a second antibody transiently raised the [Ca2+]i and activated calcineurin in CS-21 cells, as has been observed in normal T lymphocytes stimulated by cross-linking anti-Thy-1 mAbs. However, differing from normal T lymphocytes, CS-21 cells could grow either by the transient increase in [Ca2+]i or by the activation of protein kinase C. Furthermore, M(r) 23,000 protein-mediated cell survival of CS-21 cells was not accompanied by expression of the apoptosis-inhibiting protein bcl-2, although protein kinase C-activated cell survival was attended by bcl-2 expression. These results indicate that the M(r) 23,000 protein (Thy-1) of CS-21 lymphoma cells functions as a cell adhesion molecule capable of transducing signals of cell survival and growth that are not followed by bcl-2 expression.
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PMID:Apoptosis inhibition by anti-M(r) 23,000 (Thy-1) monoclonal antibodies without inducing bcl-2 expression. 779 3

Tyrosine kinases (TK) and G proteins act as second, messengers for intracellular signal transduction. TK activates the cascade of protein phosphorylation. G proteins are heterodimer complex with alpha, beta, and gamma subunits. PLC activated by GTP-binding alpha subunit lyses membrane phosphatidyl inositol (PI), releasing diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 releases calcium into cytoplasm to activate calcineurin, causing a NF-AT cytoplasmic factor (NF-ATc) to translocate to nucleus. DAG activates protein kinase C (PKC), which synthesizes another nuclear factor NF-ATn. When NF-ATc and NF-ATn assemble to form the complex on the promoter site of DNA, transcription of IL-2 mRNA begins. PKC also induces phosphorylation of I-kappa B to release NF-kappa B. The complex of CsA or FK506 with CyP or FKBP, respectively, inhibits the activation of calcineurin. FKBP-binding rapamycin inhibits cell proliferation and differentiation by inactivation of p70 s6 kinase. RS61443 and mizoribine influence specifically on the de novo pathway of purine biosynthesis. DSG may bind to Hsc 70 and inhibit the translocation of NF-kappa B into nucleus. FTY720 induces lymphocyte-specific apoptosis, independently on Fas-antigen expressions. by modulating bcl-2 genes.
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PMID:[Transplantation immunology and immunosuppressive drug]. 901 Aug 51

The bcl-2 protein plays an essential role in preventing cell death. Its activity is regulated through association with bcl-2 homologous and nonhomologous proteins and also by serine phosphorylation. We now report that bcl-2 can be proteolytically cleaved towards its N-terminus by a cysteine proteinase present in RL-7 lymphoma cell lysates, yielding a major product of apparent MW 20 kDa, different from the products of bcl-2 cleavage by HIV protease. Moreover, bcl-2 proteins mutated for Asp residues at positions 31 and 34 were efficiently cleaved by RL-7 cell lysates, indicating that this proteolytic activity is distinct from the caspase-3 that cleaves bcl-2 at Asp 34. This bcl-2 cleaving activity is inhibited by E-64 and is therefore distinct from the proteinases of the ICE/Ced-3 family (caspases), whereas reciprocally, ICE (caspase-1) is unable to cleave bcl-2. It is optimally active at pH 5, a feature distinguishing it from calpain, another non-ICE cysteine proteinase which has been associated with apoptosis. This novel bcl-2 cleaving protease, although constitutively present in RL-7 cells and resting peripheral blood lymphocytes (PBL) was upregulated following induction of apoptosis in RL-7 cells or mitogen activation in PBL. The N-terminus of bcl-2 which contains the BH4 domain that binds the kinase Raf-1 and the phosphatase calcineurin is essential for anti-apoptotic activity. Its cleavage might provide a novel post-translational mechanism for regulating bcl-2 function and could amplify ongoing programmed cell death.
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PMID:N-terminus cleavage of bcl-2 by a novel cellular non-ICE cysteine proteinase. 973 98

We have studied the actions of the protein phosphatase inhibitor okadaic acid (OA) on the expression of bcl-2 in HL60 human leukemia cells. OA induced downregulation of bcl-2 mRNA and protein prior to the induction of apoptosis. Downregulation of bcl-2 mRNA levels did not result from actions of OA on the bcl-2 upstream negative response element. Nuclear run-off analyses confirmed that OA did not affect bcl-2 gene transcription. However, OA caused a rapid increase in the rate of degradation of bcl-2 mRNA. Therefore, OA induces down-regulation of bcl-2 expression via destabilization of its transcript. The constitutive action of an OA-sensitive protein phosphatase may therefore maintain HL60 cell survival by blocking bcl-2 mRNA degradation.
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PMID:Okadaic acid-induced apoptosis of HL60 leukemia cells is preceded by destabilization of bcl-2 mRNA and downregulation of bcl-2 protein. 976 7

Synthetic ceramides induce apoptotic death of Jurkat and HL60 leukaemia cell lines. By contrast we show here that ceramide induces non-apoptotic killing of malignant cells from patients with B-chronic lymphocytic leukaemia (B-CLL) and of normal B lymphocytes. The protein phosphatase inhibitor okadaic acid readily induces apoptosis of B-CLL cells, indicating that this death pathway is fully functional in these cells. The ability of ceramide to activate the apoptotic protease caspase 3 in HL60 cells but not in B-CLL cells, as well as the lack of correlation of ceramide-mediated killing of different B-CLL isolates with expression of the apoptosis-regulating proteins bcl-2 and bax reinforce the conclusion that ceramide killing of B-CLL cells is by a non-apoptotic mechanism. Fludarabine treatment or gamma-irradiation of B-CLL cells resulted in ceramide elevation and in killing by both apoptotic and non-apoptotic mechanisms, suggesting that a ceramide-triggered non-apoptotic mechanism may play a role in the killing of these cells. Therefore, the results here show that ceramide can induce either apoptotic or non-apoptotic death, depending on the cellular context. The inability of synthetic dihydroceramide to kill B-CLL cells or normal B lymphocytes suggests that non-apoptotic killing by ceramide is via interaction with a specific, but unidentified, cellular target.
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PMID:Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism. 1022 1

It is well known that human leukemia cells, such as HL-60 and U937 are sensitive to antitumor drugs, but human normal lung fibroblasts, such as WI-38 cells are resistant to the drugs. However, the mechanisms of the different responses to apoptosis in these cell lines remain unclear. We report here that an increase of Fas and Fas ligand (FasL) expression was required for antitumor drug-induced apoptosis in WI-38 and baby hamster kidney (BHK) cells, but not in HL-60 cells. Then, we used BHK cells transfected with the bcl-2 gene to investigate the involvement of complex formation of Bcl-2 and calcineurin. Calcineurin was imported to the nucleus in response to the drug treatment. Overexpression of Bcl-2 and cyclosporin A treatment inhibited the nuclear import and FasL expression, and as a result, both inhibited apoptosis. Although a caspase inhibitor, z-Asp-CH2-DCB, suppressed the drug-induced apoptosis, it failed to inhibit the drug-induced expression of Fas and FasL. These findings suggest that initially the Fas / FasL system is activated by calcineurin-dependent transcription followed by activation of the downstream caspase cascade resulting in antitumor drug-induced apoptosis in BHK cells, but not in HL-60 cells. Furthermore, Bcl-2 inhibits the nuclear import of calcineurin and suppresses calcineurin-mediated FasL expression during antitumor drug-induced apoptosis.
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PMID:Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-treated baby hamster kidney cells. 1092 Feb 78

We report here that activation of the caspase-3 apoptotic cascade in spinal cord injury is regulated, in part, by calcineurin-mediated BAD dephosphorylation. BAD, a proapoptotic member of the bcl-2 gene family, is rapidly dephosphorylated after injury, dissociates from 14-3-3 in the cytosol, and translocates to the mitochondria of neurons where it binds to Bcl-x(L). Pretreatment of animals with FK506, a potent inhibitor of calcineurin activity, or MK801, an NMDA glutamate receptor antagonist, blocked BAD dephosphorylation and abolished activation of the caspase-3 apoptotic cascade. These findings extend previous in vitro observations and are the first to implicate the involvement of glutamate-mediated calcineurin activation and BAD dephosphorylation as upstream, premitochondrial signaling events leading to caspase-3 activation in traumatic spinal cord injury.
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PMID:Calcineurin-mediated BAD dephosphorylation activates the caspase-3 apoptotic cascade in traumatic spinal cord injury. 1100 81

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.
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PMID:Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. 1115 56


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