Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin-3 (IL-3)-dependent murine bone marrow-derived cell line FDC-P2/185-4 (185-4) undergoes apoptosis when IL-3 is withdrawn from culture medium. Previous results from our studies indicated that a high concentration of aggregated mouse IgG prevented apoptosis of 185-4 cells through Fc gammaRIII by an autocrine mechanism, producing IL-3. But after 24 hours, 185-4 cells expressed CD95 (Fas/Apo-1) on their surfaces on stimulation via Fc gammaRIII. In addition, this CD95 was functional and apoptosis was induced by anti-CD95 monoclonal antibody (MoAb). We investigated how these conflicting effects were induced by Fc gammaRIII stimulation within the context of cell survival and death. The results showed that IL-3 was induced by calcium ionophore and that the IL-3 induced by Fc gammaRIII stimulation was blocked by EGTA or FK506, but not by staurosporine (protein kinase C [PKC] inhibitor), indicating the important role of calcium-calcineurin in this system. On the other hand, the CD95 expression induced by Fc gammaRIII stimulation was blocked by staurosporine, but not by EGTA or FK506, and phorbol myristate acetate (PMA) induced CD95 expression in the same manner as Fc gammaRIII, indicating the involvement of PKC in the CD95 expression induced by Fc gammaRIII stimulation. Thus, Fc gammaRIII-mediated stimulation even while promoting immediate survival of the bone marrow cells, also triggers mechanisms that will facilitate their eventual deletion at the end of the response. These results suggest that a balance between cell survival and death is maintained to avoid unlimited cell growth caused by Fc gammaRIII-ligand interaction in hematopoiesis during inflammation.
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PMID:Fc gammaRIII-mediated regulation of hematopoiesis in murine bone marrow cells by interleukin-3 and CD95 (Fas/Apo-1). 929 24

Interleukin 3 (IL-3) stimulates the net growth of murine factor-dependent NSF/N1.H7 and FDC-P1/ER myeloid cells by stimulating proliferation and suppressing apoptosis. Recently, we discovered that Bcl2 is phosphorylated at an evolutionarily conserved serine residue (Ser70) after treatment with the survival agonists IL-3 or bryostatin 1, a potent activator of protein kinase (Ito, T., Deng, X., Carr, B., and May, W. S. (1997) J. Biol. Chem. 272, 11671-11673). In addition, an intact Ser70 was found to be required for Bcl2's ability to suppress apoptosis after IL-3 withdrawal or toxic chemotherapy. We now show that phosphorylation of Bcl2 occurs rapidly after the addition of agonist to IL-3-deprived cells and can be reversed by the action of an okadaic acid (OA)-sensitive phosphatase. A role for protein phosphatase (PP) 2A as the Bcl2 regulatory phosphatase is supported by several observations: 1) dephosphorylation of Bcl2 is blocked by OA, a potent PP1 and PP2A inhibitor; 2) intracellular PP2A, but not PP1, co-localizes with Bcl2; 3) the purified PP2Ac catalytic subunit directly dephosphorylates Bcl2 in vitro in an OA-sensitive manner; 4) the purified PP2Ac catalytic subunit preferentially dephosphorylates Bcl2 in vitro compared with PP1 and PP2B; 5) reciprocal immunoprecipitation studies indicate a direct interaction between PP2A and hemagglutinin (HA)-Bcl2; and 6) treatment of factor-deprived cells with bryostatin 1 dramatically increases the association between PP2A and Bcl2. Increased association between Bcl2 and PP2A occurs 15 min after agonist stimulation when Bcl2 phosphorylation has peaked and immediately before dephosphorylation. An agonist-induced increased association of PP2A and Bcl2 fails to occur in cells expressing the inactive, phosphorylation-negative S70A Bcl2 mutant, which indicates that an intact Ser70 site is necessary and sufficient for the interaction to occur. Functional phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.
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PMID:Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. 985 76

Interleukin-3 (IL-3)-dependent myeloid progenitor cell FDC.P2 is induced to undergo apoptotic cell death upon IL-3 depletion. Extracellular adenosine triphosphate (ATP) was found to prevent apoptosis and maintain cell viability of FDC.P2 cells upon IL-3 withdrawal. The antiapoptotic effect of ATP required extracellular Ca2+. Furthermore, FK506, a specific inhibitor of calcium/calmodulin-dependent protein phosphatase calcineurin, inhibited the antiapoptotic effect of ATP. As one of cytokines whose expression is dependent on the activation of calcineurin, interleukin-4 (IL-4) played a critical role in ATP-mediated cell survival of FDC.P2 cells because neutralizing antibody against IL-4 effectively abrogated the antiapoptotic activity of ATP. Moreover, ATP treatment induced a significant amount of secreted IL-4 that was sufficient to maintain cell viability. Taken together, our present results demonstrate that extracellular ATP triggers autocrine production of IL-4 through calcium-dependent activation of calcineurin and secreted IL-4 substitutes IL-3 in protecting FDC.P2 cells from apoptosis even in the absence of IL-3.
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PMID:Extracellular ATP inhibits apoptosis and maintains cell viability by inducing autocrine production of interleukin-4 in a myeloid progenitor cell line. 1518 34