Unknown,Transcriptomics,Genomics,Proteomics

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Zebrafish: Estrogen induced gene expression

ABSTRACT: We performed microarray experiment on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis with human E2 responsive genes revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of ER binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated ER mediated down-regulation certain genes followed by up-regulation cell cycle-related genes is highly conserved. Our study provides first evidence of molecular conservation of estrogen-responsiveness between zebrafish and human cancer cell lines, hence demonstrating the potential of zebrafish for estrogen-related cancer research. 10 samples were analyzed in total. Three samples in control, 3 samples treated with estrogen and 3 samples treated with estrogen in combination with ICI.

ORGANISM(S): Danio rerio

SUBMITTER: Justin Joseph Gnanakkan

PROVIDER: E-GEOD-27707 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a M-bM-^@M-^\rapidM-bM-^@M-^] non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear. Methods and Results: Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in E2-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of E2 to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury. Conclusions: Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents. Transgenic disrupting peptide mice (DPM) express the Estrogen Receptor (ER) alpha amino acids 176-253 peptide under CMV promoter control. This peptide blocks interactions between ER and striatin, which inhibits rapid non-genomic signaling by ER to cellular kinases. Female WT and DPM mice (4 mice per sample) were overiectomized, and 1 week later aortas were harvested and treated + 10 nM beta-estradiol (E2) or + EtOH vehicle (Veh) for 4 hrs ex vivo. Total RNA was collected, reverse transcribed to cDNA and used to probe Affymetrix mouse 430.A 2.0 arrays.

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Zebrafish: Estrogen induced gene expression

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