title: Liganded ERα Stimulates the E3 Ubiquitin Ligase Activity of UBE3C to Facilitate Cell Proliferation.
abstract: Estrogen receptor (ER)α is a well-characterized ligand-dependent transcription factor. However, the global picture of its nongenomic functions remains to be illustrated. Here, we demonstrate a novel function of ERα during mitosis that facilitates estrogen-dependent cell proliferation. An E3 ubiquitin ligase, UBE3C, was identified in an ERα complex from estrogen-treated MCF-7 breast cancer cells arrested at mitosis. UBE3C interacts with ERα during mitosis in an estrogen-dependent manner. In vitro, estrogen dramatically stimulates the E3 activity of UBE3C in the presence of ERα. This effect was inhibited by the estrogen antagonist tamoxifen. Importantly, estrogen enhances the ubiquitination of cyclin B1 (CCNB1) and destabilizes CCNB1 during mitosis in a manner dependent on endogenous UBE3C. ERα, UBE3C, and CCNB1 colocalize in prophase nuclei and at metaphase spindles before CCNB1 is degraded in anaphase. Depletion of UBE3C attenuates estrogen-dependent cell proliferation without affecting the transactivation function of ERα. Collectively, these results demonstrate a novel ligand-dependent action of ERα that stimulates the activity of an E3 ligase. The mitotic role of estrogen may contribute to its effects on proliferation in addition to its roles in target gene expression.
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ohtake
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Takana
authors.affiliation: Department of Translational Oncology (M.O., W.W., T.O.), Institute of Advanced Medical Science (H.N.), St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan; Institute of Molecular and Cellular Biosciences (M.O.), University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Cellular and Molecular Toxicology (F.O.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan; and Laboratory of Protein Metabolism (Y.S., K.T.), Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000705:Anaphase / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D056744:Cyclin B1 / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008938:Mitosis; D008941:Spindle Apparatus / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C534699:CCNB1 protein, human; D056744:Cyclin B1; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; C555759:UBE3C protein, human; D044767:Ubiquitin-Protein Ligases