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      Suppression of Lymphocyte Mitogenesis by Tamoxifen: Studies on Protein Kinase C, Calmodulin and Calcium

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          The effect of tamoxifen (TX; 1.0 μ M) on the mitogenic response of rat lymphocytes was compared with the effect of drugs that are known to act on protein kinase C (PKC), calmodulin (CM), and calcium (Ca<sup>2+</sup>). The calcium ionophore A23187 (0.2 μ M) was mitogenic on its own which was not influenced by TX. The agents modulating PKC or CM (phorbol-myristate-13-acetate; R24571, chlorpromazine) influenced mitogenesis differently than did TX. General inhibition of lymphocyte proliferation was seen with the Ca<sup>2+</sup> antagonist agents (EGTA, TMB-8) as with TX. The antiproliferative effect of TX was partially reversed by the increase of Ca<sup>2+</sup> in the culture medium when T cell mitogens were used, but not in the case of lipid A, a B lymphocyte mitogen. However, the concanavalin A-induced Ca<sup>2+</sup> influx was further elevated by TX which differed from the effect of the Ca<sup>2+</sup> channel-blocking agent verapamil. The results suggest that TX resets the threshold stimulus necessary for mitogenesis and is completely reversible.

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          Most cited references 6

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          Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.

          The Fas antigen (Fas) belongs to the tumor necrosis factor (TNF)/nerve growth factor receptor family, and it mediates apoptosis. Using a soluble form of mouse Fas, prepared by fusion with human immunoglobulin Fc, Fas ligand was detected on the cell surface of a cytotoxic T cell hybridoma, PC60-d10S. A cell population that highly expresses Fas ligand was sorted using a fluorescence-activated cell sorter, and its cDNA was isolated from the sorted cells by expression cloning. The amino acid sequence indicated that Fas ligand is a type II transmembrane protein that belongs to the TNF family. The recombinant Fas ligand expressed in COS cells induced apoptosis in Fas-expressing target cells. Northern hybridization revealed that Fas ligand is expressed in activated splenocytes and thymocytes, consistent with its involvement in T cell-mediated cytotoxicity and in several nonlymphoid tissues, such as testis.
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            Effect of tamoxifen, a nonsteroidal antiestrogen, on phospholipid/calcium-dependent protein kinase and phosphorylation of its endogenous substrate proteins from the rat brain and ovary.

            Antiestrogens (tamoxifen, clomiphene and nafoxidine) were found to inhibit phospholipid/Ca2+-dependent protein kinase (PL/Ca-PK, or protein kinase C), whereas estrogens (estradiol and diethylstilbesterol) and the weakly estrogenic chlorotrianisene were inactive. Kinetic analysis indicated that the antiestrogens inhibited PL/Ca-PK competitively with respect to phosphatidylserine (Ki = 16-27 microM), but non-competitively with Ca2+ (Ki = 14-30 microM). Tamoxifen, but not diethylstilbesterol, also inhibited the phospholipid/Ca2+-dependent phosphorylation of various endogenous proteins from the total, solubilized fraction of the rat brain and ovary. Myosin light chain kinase, a calmodulin/Ca2+-dependent class of protein kinase, was similarly inhibited by tamoxifen; the drug, however, was without effect on cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It is suggested that PL/Ca-PK, by virtue of the hydrophobic interactions required for the enzyme activation, may represent a potential site of action for the lipophilic antiestrogens, in addition to the commonly recognized intracellular estrogen receptors.
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              Immunomodulation by tamoxifen and pergolide.

              Treatment of rats with tamoxifen citrate or pergolide mesylate was as effective in inhibiting antibody formation and contact sensitivity skin reactions as was hypophysectomy. The immunocompetence of tamoxifen citrate- and pergolide mesylate-suppressed animals could be fully restored by additional treatment with prolactin or growth hormone.

                Author and article information

                S. Karger AG
                February 1999
                18 February 2000
                : 7
                : 2
                : 68-76
                aDepartment of Internal Medicine and the Manitoba Cancer Treatment and Research Foundation, bDepartment of Immunology, cDepartment of Pharmacology and Oral Biology and dDepartment of Pediatrics, Faculty of Medicine, University of Manitoba, Winnipeg, Man., Canada
                26422 Neuroimmunomodulation 2000;7:68–76
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 8, References: 42, Pages: 9
                Original Paper


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