ERα, SKP2 and E2F-1 form a feed forward loop driving late ERα targets and G1 cell cycle progression.

Estrogen triggers transactivation coupled estrogen receptor α (ERα) proteolysis, but mechanisms thereof remain obscure. Present data link estrogen:ERα-driven transcription with cell cycle progression. Although liganded ERα induces many genes within 1-4 h, gene activation after 6 h is thought to be indirect. Here, we identify SKP2 as a late-acting coactivator that drives ERα targets to promote G1-to-S progression. Data support a model in which estrogen-activated cyclin E-CDK2 binds and phosphorylates ERαS341, to prime ERα-SCF(SKP2) binding via SKP2-L248QTLL252 in late G1. SKP2 activates ERα ubiquitylation and proteolysis. Putative late ERα targets were identified by expression profiling. SKP2 knockdown attenuated E2F-1 and BLM induction. SKP2 overexpression, but not coactivator motif mutant SKP2-L248QTAA252, enhanced estrogen-induced E2F-1 and BLM expression. SKP2 knockdown impaired estrogen-stimulated ERα, SKP2, SRC3 and RNA polymerase II recruitment to E2F-1 and BLM promoters. This work not only identifies these late-activated genes as bona fide ERα targets but describes a novel mechanism for their periodic activation. SKP2 serves as dual ERα E3 ligase/coactivator for late-activated target genes, revealing a novel mechanism whereby ERα/SCF(SKP2) transactivation of E2F-1 feeds forward to drive G1-to-S.