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Molecular mechanisms of ligand-dependent repression by the estrogen receptor and derepression by inflammatory signaling


Uncovering the linkage between inflammatory signaling pathways and transcriptional regulatory programs is key to understanding the role of inflammation in homeostasis and disease. An intriguing aspect of this connection has emerged with the identification of a cohort of genes that exhibit direct negative regulation by liganded ER[alpha] that can be reactivated by specific inflammatory signals. We found that ER[alpha]-dependent repression of the BMP7 gene, which is overexpressed in up to 70% of primary breast tumors and is reactivated by inflammatory signaling, utilizes an LXXLL motif-containing orphan nuclear receptor, SHP, as a corepressor to recruit the NCoR/TAB2 complex to the BMP7 promoter. In response to inflammatory signals, transient association of the ubiquitin ligases TRAF6 and Ubc13 with the TAB2-containing NCoR complex on the BMP7 promoter catalyzes K63-linked polyubiquitination of TAB2, permitting promoter-specific recruitment of MEKK1 and licensing clearance of the NCoR complex. We have identified similar inflammation-induced reactivation of additional ER[alpha]-repressed genes, including BAK1, NCOA3, and ZNF217, which also exhibit TRAF6-dependent derepression. We suggest that this TAB2/TRAF6/MEKK1 corepressor clearance pathway regulates specific gene expression programs in response to diverse stimuli and in other cell types, including the hematopoietic and nervous systems, identifying a novel pathway for selective gene activation by inflammatory signals

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