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      Activating Transcription Factor 3 Is Estrogen-Responsive in utero and Upregulated during Sexual Differentiation

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          Background/Aims: Synthetic estrogens induce hypospadias, an anomaly of genital tubercle/urethral development. Activating transcription factor 3 (ATF3), which is estrogen-responsive in vitro, is upregulated in hypospadiac human tissue. We used a mouse model of steroid-dependent genital tubercle development to elucidate the ontogeny of ATF3 expression and the developmental response of ATF3 in vivo to estrogen exposure. Methods: We used quantitative RT-PCR to assess ontogenic expression of ATF3 and its response to estrogen treatment in utero. Immunohistochemistry was used to localize the protein. Results: Quantitative RT-PCR showed that ATF3 mRNA is upregulated in all estrogen-exposed fetal genital tubercles compared to controls (p = 0.024), including specifically in males exposed in utero (p = 0.049). Additionally, its expression increases significantly during the period of sexual differentiation in both sexes and significantly correlates with female development (p = 0.004), a phenomenon that appears to be attributable to higher levels at birth in females. The protein localizes in the nucleus, as expected. Conclusions: ATF3 is estrogen-responsive in vivo. The response of ATF3 to estrogenic stimulation in utero at an earlier stage may contribute to urethral abnormalities observed in estrogen-exposed male fetuses, although it is likely not the only gene involved, which supports the general understanding that hypospadias is subject to multifactorial influences. ATF3 may therefore be an appropriate gene for further investigations in an endocrine context.

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          Most cited references 7

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          Development of cDNA microarray for expression profiling of estrogen-responsive genes.

          Estrogen plays an important role in many physiological events including carcinogenesis and the development of human breast cancer. However, the molecular mechanisms of estrogen signaling in cancers have not been clarified hitherto and accurate therapeutic prediction of breast cancer is earnestly desired. We first carried out estrogen-responsive expression profiling of approximately 9000 genes in estrogen receptor-positive human MCF-7 breast cancer cells. Based on the results, estrogen-responsive genes were selected for production of a custom-made cDNA microarray. Using a microarray consisting of the narrowed-down gene subset, we first analyzed the time course of the estrogen-responsive gene expression profiles in MCF-7 cells, resulting in subdivision of the genes up-regulated by estrogen into early-responsive and late-responsive genes. The expression patterns of several genes were confirmed by Northern blot analysis. We also analyzed the effects of the estrogen antagonists ICI 182780 and 4-hydroxytamoxifen (OHT) on the estrogen-responsive gene expression profiles in MCF-7 cells. While the regulation of most of the genes by estrogen was completely abolished by ICI 182780, some genes were partially regulated by estrogen even in the presence of OHT. Furthermore, the estrogen-responsive gene expression profiles of twelve cancer cell lines derived from the breast, ovary, stomach and other tissues were obtained and analyzed by hierarchical clustering including the profiles in MCF-7 cells. Several genes also showed up-regulation or down-regulation by estrogen in cell lines other than MCF-7 cells. The significance of the estrogen-responsive genes identified in these analyses concerning the nature of cancer is discussed.
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            Integration of the non-genomic and genomic actions of estrogen. Membrane-initiated signaling by steroid to transcription and cell biology.

            Estrogen binds to receptors that translocate to the plasma membrane and to the nucleus. The rapid, non-genomic actions of this sex steroid are attributed to membrane action, while gene transcription occurs through nuclear receptor function. However, gene transcription can also result from estrogen signaling initiated at the membrane, but the relative importance of this mechanism is not known. In vascular endothelial cells (EC), estradiol (E(2)) activates several kinase cascades, including phosphatidylinositol 3-phosphate (PI3K)/Akt, a signaling pathway that impacts EC biology. We determined here by DNA microarray that 40-min exposure to E(2) significantly increased 250 genes in EC, up-regulation that was substantially prevented by the PI3K inhibitor, LY294002. This coincided with maximum E(2)-induced PI3K activity at 15-30 min. An important vascular gene strongly up-regulated by E(2) in our array produces cyclooxygenase-2 (Cox-2). In cultured EC, E(2) induced both Cox-2 gene expression and new Cox-2 protein synthesis by 40 and 60 min, respectively, and rapidly stimulated the secretion of prostaglandins PGI(2) and PGE(2). The up-regulation of gene expression reflected transcriptional transactivation, shown using Cox-2 promoter/luciferase reporters in the EC. Soluble inhibitors or dominant negative constructs for PI3K and Akt prevented all these actions of E(2). Functionally, EC migration was induced by the sex steroid, and this was significantly reversed by NS-398, a Cox-2 inhibitor. Gene transcription and cell biological effects of estrogen emanate from rapid and specific signaling, integrating cell surface and nuclear actions of this steroid.
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              Hypospadias and urethral development.

               L Baskin (2000)
              Hypospadias is a common congenital anomaly that may be treated with surgical reconstruction. In the majority of cases the etiology remains elusive. Although androgens are clearly critical for penile development, defects in androgen metabolism and/or the androgen receptor explain only a small subset of cases of hypospadias. Strategies are presented for understanding the etiology of hypospadias. Current scientific reports on the etiology of hypospadias were reviewed, and the embryology and possible mechanisms of urethral and penile formation are presented. A new theory of glandular human urethral development via endodermal cellular differentiation is proposed to replace the classic explanation of ectodermal intrusion. Careful studies of penile and urethral development have led to a better understanding of genital embryology. Future areas of study, such as endocrine disrupters, mesenchymal-epithelial interactions and mechanisms of penile growth, are proposed to explain the etiology of hypospadias.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2006
                22 May 2006
                : 65
                : 5
                : 217-222
                Center for the Study and Treatment of Hypospadias, Department of Urology, University of California, San Francisco, Calif., USA
                92402 Horm Res 2006;65:217–222
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 2, References: 12, Pages: 6
                Original Paper


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