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

Oncogene volume 33, pages 2341–2353 (2014)Cite this article

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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-SCFSKP2 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/SCFSKP2 transactivation of E2F-1 feeds forward to drive G1-to-S.

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Acknowledgements

We thank M Pagano for bacculovirus stocks (CUL1, SKP1, RBX1, SKP2), WL Kraus for pPK-FLAG-ERα plasmid, H-K Lin for pcDNA4-His-Max-Xpress SKP2, and J Sun for technical intellectual input. This work was supported by NIH R01CA123415 (JMS and ZN), and a US DOD Pre-doctoral grant W81XWH-11-1-0097 (WZ).

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Authors and Affiliations

  1. Braman Family Breast Cancer Institute, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA

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

  2. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA

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

  3. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    J M Slingerland

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Correspondence to J M Slingerland.

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Zhou, W., Srinivasan, S., Nawaz, Z. et al. ERα, SKP2 and E2F-1 form a feed forward loop driving late ERα targets and G1 cell cycle progression. Oncogene 33, 2341–2353 (2014). https://doi.org/10.1038/onc.2013.197

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