title: BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells.
abstract: We recently reported that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby causing a loss of function of the PHB2 tumor suppressor in the nuclei of breast cancer cells. However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2-dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ERα). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ERα signals in breast cancer cells.
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan; Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Nam-Hee
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.affiliation: National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Matsuo
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyoshi
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, Tokushima Breast Care Clinic, Tokushima, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Sasa
authors.affiliation: National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002522:Chlorocebus aethiops; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D000091402:Prohibitins; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D028901:alpha Karyopherins / Q000378:metabolism*
chemical_list: C000595370:ARFGEF3 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D020662:Guanine Nucleotide Exchange Factors; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D028901:alpha Karyopherins