title: ERα, SKP2 and E2F-1 form a feed forward loop driving late ERα targets and G1 cell cycle progression.
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-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.
authors.affiliation: 1] Braman Family Breast Cancer Institute, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA [2] Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: W
authors.identifier: 0000000254965815
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 1] Braman Family Breast Cancer Institute, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA [2] Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: 1] Braman Family Breast Cancer Institute, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA [2] Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Nawaz
authors.affiliation: 1] Braman Family Breast Cancer Institute, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA [2] Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA [3] Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Slingerland
mesh_terms: D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D019927:Cyclin E; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D044786:S-Phase Kinase-Associated Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D012319:RNA Polymerase II; C097151:Bloom syndrome protein; D053484:RecQ Helicases