Modulation of Genomic and Non-Genomic Signaling Pathways by Xenoestrogens
PI: Tara Sabo-Attwood, Ph.D.
Co-I: P. Lee Ferguson, Ph.D.
This project addresses the potential role of non-genomic estrogen signaling in novel mechanisms of endocrine disruption. Xenoestrogenic compounds are known to act on vertebrate organisms by altering the activity of 17-?-estradiol (E2) at nuclear estrogen receptors (ERs), proteins that form a transcriptional complex that regulates the expression of downstream genes. Although activation or repression of ER activity is a known, genomic-driven mechanism of xenoestrogen action, it does not fully capture the vastly different phenotypic responses of organisms exposed to xenoestrogens. Recently, a membrane receptor, known as the G-protein coupled estrogen receptor (GPER/GPR30) has been implicated in estrogen-responsive, nongenomic signaling pathways, which act through a series of kinase-mediated cascades. GPER therefore represents an alternate and novel estrogen response mechanism that could be a sensitive target of modulation by xenoestrogens. It is likely that opposing, and in some cases convergent crosstalk between the ERs and GPER could occur upon xenoestrogen exposure. Although a number of distinct mechanisms could explain this action, possibilities include; an ‘ER-targeted’ mechanism whereby GPER stimulates kinase activity that acts directly on ERs and/or coregulatory proteins by controlling phosphorylation events that modulate ER-complex activity; ‘ER-non-targeted’ pathways that activate kinases that lead to gene expression independently of ERs. Based on this premise, we hypothesize that GPER acts through kinase-mediated mechanisms to modulate both nuclear-ER-dependent and -independent signaling pathways in a xenoestrogen-specific manner. We intend to test this hypothesis using an integrated functional proteomic and molecular biology approach to address 3 specific aims; (1) Characterize the impact of xenoestrogens on ER and GPER binding, activation and cellular endpoints in lung and breast cells; (2) Assess the influence of xenoestrogens acting through ERs and GPER on kinase activity toward nuclear ER transcriptional complexes and global cell proteins; (3) Assess the role of ERs and GPER in xenoestrogen-initiated phosphorylation of select ER coregulatory proteins in complex recruitment through defined kinase pathways. The expected outcomes will reveal whether ERs and GPER contribute collectively and/or independently to differential gene regulation and cellular processes impacted by xenoestrogens. This contribution is significant, as results illuminate mechanisms by which xenoestrogens act through distinct receptors, highlighting a potentially novel and highly relevant mechanism of endocrine disruption.
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