Estrogenic signaling upstream and downstream of mTOR

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Abstract Work in the Holz lab focuses on the crosstalk between estrogen signaling and mTOR (mechanistic target of rapamycin), two fundamental pathways that regulate growth and proliferation in the cell. One of the major unanswered questions is how cytoplasmic signaling by estrogen activates mTOR, and what downstream mTOR effectors are the specific targets of estrogen. This question represents a major gap in our understanding of the relationship between estrogen and mTOR signaling, with relevance to normal cell homeostasis and inappropriate signaling in many estrogen-dependent diseases. Two related projects stem from our published and preliminary data. First, we will examine how mTOR is activated by estrogen, and what downstream cellular events are initiated. To accomplish this goal, we will use quantitative proteomics and phosphoproteomics for signaling pathway discovery, followed by biochemical investigation and cell biology- based studies of estrogen- and mTOR-regulated proteins. Second, we will investigate the control of protein synthesis by estrogen. While regulation of transcription by estrogen is well studied, we propose to investigate an unexplored role for estrogen in mediating translational control. We will employ polysome profiling coupled with RNA-seq to identify translationally regulated estrogenic targets. The proposed research program will combine our interests in estrogen signaling and mTOR-regulated translational control, will allow us to freely generate new data and to explore exciting directions.