Progesterone Receptor Scaffolding Function in Breast Cancer
نویسندگان
چکیده
1 Progesterone receptors (PR) are critical mediators of mammary gland development and 2 contribute to breast cancer progression. Progestin-induced rapid activation of 3 cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by 4 phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck25 dependent and progestin-regulated in intact cells, but also occurs in the absence of PR 6 ligands, when cells enter the G1/S phase of the cell cycle. T47D breast cancer cells 7 stably expressing a PR-B mutant that cannot be phosphorylated at Ser81 (S81A) 8 formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, 9 also required Ser81 phosphorylation for basal and/or progestin-regulated (BIRC3, 10 HSD11β2, and HbEGF) expression. Additionally, wt PR-B, but not S81A mutant PR, 11 was robustly recruited to a PRE-containing transcriptional enhancer region of BIRC3; 12 abundant ck2 also associated with this region in cells expressing wt but not S81A PR. 13 We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and 14 regulation of selected PR-B target genes. Understanding how PR functions in the 15 context of high kinase activities characteristic of breast cancer is critical to 16 understanding the basis of tumor-specific changes in gene expression and will speed 17 the development of highly selective treatments. 18
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تاریخ انتشار 2010