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      Androgen-Dependent Expression of c-jun and c-fos in Human Non-Transformed Epithelial Prostatic Cells: Association with Cell Proliferation

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          Objective: To assess the effect of dihydrotestosterone (DHT) on the gene expression of c-fos and c-jun and on the proliferation of human non-transformed epithelial prostatic (HNTEP) cells. Methods: Cell proliferation (MTT) and c-fos and c-jun mRNA expression (RT-PCR) were determined in cells treated with DHT (10<sup>–8</sup>, 10<sup>–10</sup>, and 10<sup>–13</sup> M) or with control medium. Results: DHT 10<sup>–13</sup>  M had a significant stimulatory effect on cell proliferation (p < 0.05) and c-fos and c-jun gene expression when compared to cells treated with higher concentrations of this hormone (10<sup>–10</sup> and 10<sup>–8</sup> M) or with the control group. Conclusions: Our data demonstrate that the increase in c-fos and c-jun expression and cell growth in HNTEP cells is maximal with the lowest DHT concentration (10<sup>–13</sup> M). These proto-oncogenes may play a role in the control of hormone responsiveness and cell proliferation in HNTEP cells.

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          Most cited references 11

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          Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c-Jun in the human prostate cancer cell line LNCaP.

          In exploring the possible mechanisms of androgen independence of prostate-specific antigen (PSA) gene expression, we investigated the effect of elevating AP-1 by both 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment and transfection of the c-Jun expression vector in LNCaP cells. Transcription of PSA is initiated when ligand-activated androgen receptor (AR) binds to a region in the PSA promoter that contains an androgen-responsive element (ARE). It was found that TPA inhibited androgen-induced PSA gene expression by a mechanism that did not alter nuclear levels of AR protein. Overexpression of AP-1 (jun and fos proteins) also inhibited androgen-induced PSA promoter activity. These observations were apparently related to the disruption of AR.ARE complexes as demonstrated by the results of electrophoretic mobility shift assays. Specifically, c-Jun inhibited the formation of AR.ARE complexes and conversely that AR-glutathione S-transferase proteins inhibited the formation of c-Jun.TPA-responsive element (TRE) complexes. Consistent with the inhibitory effect of both proteins, anti-c-Jun antibody blocked the inhibition of AR.ARE complex formation by c-Jun. A similar, but less marked, effect was obtained when anti-AR antibody was used to prevent AR inhibition of c-Jun.TRE complex formation. These findings together with results obtained from co-immunoprecipitation experiments strongly suggest that mutual repression of DNA binding activity is due to direct interaction between the two proteins and that the degree of repression may be determined by the ratio of AR to c-Jun. The mechanism of repression studied in mutant analysis experiments yielded evidence of an interaction between the DNA- and ligand-binding domains of AR and the leucine zipper region of c-Jun. Thus, the AR is similar to other nuclear receptors in its ability to interact with AP-1. This association provides a link between AP-1 and AR signal transduction pathways and may play a role in the regulation of the androgen-responsive PSA gene.
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            GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells.

            Bombesin (BN) and its mammalian homologue gastrin-releasing peptide (GRP) have been shown to play an important role in human cancer as autocrine and paracrine growth factors. Prostatic neuroendocrine cells are thought to secrete these regulatory peptides and they may therefore interact with their specific, aberrantly expressed GRP receptor (GRP-R) in prostate cancer. In this study, we investigated the effect of BN on immediate early gene expression in two androgen-independent prostate cancer cell lines DU-145 and PC-3 with functional GRP receptor. We found that BN induced c-fos mRNA expression in both cell lines in a time-dependent manner. In contrast, c-jun mRNA was only modestly induced in DU-145 cells but not at all in PC-3 cells. On the protein level, we detected BN-induced stimulation of the c-fos gene product but not of c-jun protein. Sustained increase of the c-myc gene product was detectable in PC-3 but not in DU-145 cells. Concurrently, we demonstrated BN-dependent activation of the transcription factor Elk-1 and significant increase of cell proliferation in both prostate cancer cell lines. Taken together, these data suggest that BN acts as a mitogen in prostate cancer and this might be associated with the activation of the transcription factor Elk-1 and the immediate early gene c-fos.
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              Androgen-induced proliferative quiescence in prostate cancer cells: The role of AS3 as its mediator


                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                19 November 2003
                : 60
                : 5
                : 209-214
                aDepartment of Physiology, Universidade Federal do Rio Grande do Sul, and bGynecological Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
                74033 Horm Res 2003;60:209–214
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 27, Pages: 6
                Original Paper


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