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

W. Zhou, S. Srinivasan, Z. Nawaz, J. M. Slingerland

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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-L 248 QTLL 252 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-L 248 QTAA 252, 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.

Original languageEnglish (US)
Pages (from-to)2341-2353
Number of pages13
JournalOncogene
Volume33
Issue number18
DOIs
StatePublished - May 1 2014

Keywords

  • Coactivator
  • Cyclin E-CDK2
  • E2F-1
  • ERα
  • Ubiquitylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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