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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; Germany ; KINASE ; GENE ; GENE-EXPRESSION ; PROTEIN ; DIFFERENTIATION ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; MESSENGER-RNA ; DOMAIN ; mechanisms ; DOWN-REGULATION ; PHOSPHORYLATION ; PROTEIN-KINASE ; signal transduction ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; SIGNAL-TRANSDUCTION ; CANCER-CELLS ; CARCINOMA-CELLS ; LOCALIZATION ; PROTEIN-KINASE-C ; PHORBOL ESTER ; ESTRADIOL ; SYNTHASE ; TRANSFECTION ; regulation ; ESTROGEN ; estrogen receptor ; GLYCOGEN-SYNTHASE KINASE-3 ; GSK3 ; MCF-7 CELLS ; PKC ; PKC delta
    Abstract: Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKC delta is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKC delta on the regulation of the transcriptional activity of the human ER alpha. By using 12-O-tetradecanoylphorbol- 13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKC delta is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKC delta by TPA resulted in activation and nuclear translocation of ER alpha and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RD delta of PKC delta, which is inhibitory to PKC delta, inhibited the TPA-induced ER alpha activation and translocation. ER alpha was not phosphorylated by PKC delta; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKC delta. The expression of RD delta resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKC delta-related nuclear translocation of ER alpha
    Type of Publication: Journal article published
    PubMed ID: 15824731
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  • 2
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; carcinoma ; Germany ; human ; HYBRIDIZATION ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; PATIENT ; FAMILY ; MARKER ; hormone ; IN-SITU ; PROGRESSION ; immunohistochemistry ; PATTERNS ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; BENIGN ; GLYCATION END-PRODUCTS ; RAGE ; CARCINOMAS ; adenocarcinoma ; intraepithelial neoplasia ; NEURITE OUTGROWTH ; KAPPA-B ; CANCER PATIENTS ; HEALTHY ; prostate carcinoma ; OXIDANT STRESS ; SERUM ; in situ hybridization ; ELISA ; RE ; END ; TUMORIGENESIS ; HUMAN PROSTATE ; HYPERPLASIA ; TUMOR TISSUE ; MOLECULAR-GENETICS ; HUMAN-PROSTATE ; S100 PROTEINS ; EXPRESSION PATTERNS ; SERUM-LEVELS ; TUMOR DIFFERENTIATION
    Abstract: Purpose: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S10OA8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. Experimental Design:Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S10OA8, S100A9, and RAGE. In addition, in situ hybridization of S10OA8 and S10OA9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S10OA9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). Results: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S10OA8 and S10OA9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. Conclusion: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH
    Type of Publication: Journal article published
    PubMed ID: 16033829
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; human ; KINASE ; PATHWAY ; PATHWAYS ; PROSTATE ; VITRO ; PROTEIN ; PROTEINS ; cell line ; LINES ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; FAMILY ; BIOLOGY ; CELL-LINES ; PHOSPHORYLATION ; ASSOCIATION ; SIGNAL ; MAP KINASE ; hormone ; prostate cancer ; PROSTATE-CANCER ; CELL-LINE ; LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; CANCER-CELLS ; US ; MIGRATION ; LIGANDS ; BENIGN ; EPITHELIAL-CELLS ; INTERMEDIATE-FILAMENTS ; RAGE ; UNITED-STATES ; NEURITE OUTGROWTH ; CALCIUM ; NF-kappa B ; TRANSLOCATION ; pathology ; cell lines ; MAP KINASES ; STATES ; CALCIUM-BINDING PROTEINS ; SUBCELLULAR-LOCALIZATION ; signaling ; PROTEIN TRANSLOCATION ; FEATURES ; ONCOLOGY ; CALCIUM-BINDING PROTEIN ; DISORDERS ; RECOMBINANT ; RE ; FAMILIES ; FUNCTIONAL IMPLICATIONS ; ENHANCED EXPRESSION ; HUMAN PROSTATE ; LEVEL ; HUMAN-PROSTATE ; S100 PROTEINS ; KINASES ; immunofluorescence ; CALCIUM-BINDING ; S100A8 ; S100A9 ; ADVANCED GLYCATION ENDPRODUCTS ; END-PRODUCTS RAGE ; function ; HORMONES ; INTRACELLULAR CALCIUM ; MAP ; PUTATIVE TUMOR-SUPPRESSOR ; S100
    Abstract: S100 proteins, a multigenic family of calcium-binding proteins, have been linked to human pathologies in recent years. Deregulated expression of S100 proteins, including S100A8 and S100A9, was reported in association with neoplastic disorders. In a previous study, we identified enhanced expression of S100A8 and S100A9 in human prostate cancer. To investigate potential functional implications of S100A8 and S100A9 in prostate cancer, we examined the influence of over-expressed and of purified recombinant S100A8 and S100A9 proteins in different prostate epithelial cell lines. S100A8 and S100A9 were secreted by prostate cancer cells, a finding which prompted us to analyze a possible function as extracellular ligands. S100A8/A9 induced the activation of NF-kappa B and an increased phosphorylation of p38 and p44/42 MAP kinases. In addition, extracellular S100A8/A9 stimulated migration of benign prostatic cells in vitro. Furthermore, in immunofluorescence experiments, we found a strong speckled co-localization of intracellular Sl00A8/A9 with RAGE after stimulating cells with recombinant S100A8/A9 protein or by increasing cytosolic Ca2+ levels. In summary, our findings show that S100A8 and S100A9 are linked to the activation of important features of prostate cancer cells. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16297907
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  • 4
    Keywords: RECEPTOR ; CELLS ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; VITRO ; SITE ; SITES ; GENE-EXPRESSION ; PROTEIN ; transcription ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; MECHANISM ; DOMAIN ; ACTIVATED PROTEIN-KINASE ; BINDING ; PHOSPHORYLATION ; PROTEIN-KINASE ; ALPHA ; hormone ; TRANSCRIPTIONAL ACTIVITY ; ASSAY ; NUMBER ; PROTEIN-KINASES ; beta-catenin ; CONSTITUTIVE ACTIVATION ; TARGETS ; RECEPTORS ; ESTRADIOL ; CELL-GROWTH ; signaling ; RE ; RESIDUES ; SYNTHASE ; KAPPA-B ACTIVATION ; regulation ; MUTATIONAL ANALYSIS ; ESTROGEN ; TRANSCRIPTIONAL ACTIVATION ; ASSAYS ; KINASES ; NUCLEAR RECEPTORS ; estrogen receptor ; GLYCOGEN-SYNTHASE KINASE-3 ; GSK3 ; INTERACT ; CHLORIDE
    Abstract: Like other steroid hormone receptors, estrogen receptor-alpha (ER alpha) is a substrate for protein kinases, and phosphorylation has profound effects on the function and activity of this receptor. A number of different kinases have been implicated in ER alpha regulation. In this report we show by mutational analysis and in vitro kinase assays that ER alpha is a substrate for glycogen synthase kinase-3 (GSK-3) in vitro and is phosphorylated on two sites, the Ser-102, -104, and -106 motif and Ser-118, both located in the N-terminal transcription activation function (AF-1) domain. GSK-3 forms a complex with ER alpha in vivo as demonstrated by co-immunoprecipitation from cell lysates. The GSK-3 inhibitor lithium chloride was used to determine the role of GSK-3 in phosphorylation of Ser-102, -104, and -106 and Ser-118 in vivo and to explore the role of these serines in the regulation of ER alpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of Ser-104 and -106 and Ser-118, which suggests these serine residues as targets for GSK-3 in vivo. Our results further suggest that ER alpha phosphorylation by GSK-3 stabilizes ER alpha under resting conditions and modulates ER alpha transcriptional activity upon ligand binding. Inhibition and constitutive activation of GSK-3, both, resulted in inhibition of ER alpha transcriptional activity, indicating a function of active as well as inactive GSK-3 in ER alpha regulation. These findings uncover a novel mechanism for the regulation of ER alpha-mediated estrogen signaling controlled by a dual action of GSK-3
    Type of Publication: Journal article published
    PubMed ID: 16076840
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