Abstract
Abstract : Estrogen triggers transactivation coupled estrogen receptor (ER ) proteolysis, but mechanisms thereof remain obscure. Present data link estrogen:ER -driven transcription with cell cycle progression. Here, we identify SKP2 as a late-acting coactivator that drives ER targets to promote G1-to-S progression. Data support a model in which estrogen-activated ER phosphorylation, to prime ER -SCFSKP2 binding in late G1. SKP2 activates ER ubiquitylation and proteolysis. Putative late ER targets were identified by expression profiling. SKP2 knockdown attenuated E2F-1 and BLM induction. SKP2 overexpression enhanced estrogen-induced E2F-1 and BLM expression. SKP2 knockdown impaired estrogen-stimulated ER , SKP2, SRC3 and RNA polymerase II recruitment to E2F-1 and BLM promoters. SKP2 serves as dual ER E3 ligase/coactivator for late-activated target genes, revealing a novel mechanism whereby ER /SCFSKP2 transactivation of E2F-1 feeds forward to drive G1-to-S.
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