title: Elevated estrogen receptor-α in VHL-deficient condition induces microtubule organizing center amplification via disruption of BRCA1/Rad51 interaction.
abstract: Since loss of VHL is frequently detected early phase genetic event in human renal cell carcinoma, pVHL is assumed to be indispensable for suppression of tumor initiation step. However, induction of HIF-1α, target of pVHL E3 ligase, is more adequate to angiogenesis step after tumor mass formation. Concerning this, it has been reported that pVHL is involved in centrosome location during metaphase and regulates ER-α signaling. Here, we provide the evidences that pVHL-mediated ER-α suppression is critical for microtubule organizing center (MTOC) maintaining and elevated ER-α promotes MTOC amplification through disruption of BRCA1-Rad51 interaction. In fact, numerous MTOC in VHL- or BRCA1-deficient cells are reduced by Fulvestrant, inhibitor of ER-α expression as well as antagonist. In addition, we reveal that activation of ER signaling can increase γ-tubulin, core factor of TuRC and render the resistance to Taxol. Thus, Fulvestrant but not Tamoxifen, antagonist against ER-α, can restore the Taxol sensitivity in VHL- or BRCA1-deficient cells. Our results suggest that pVHL-mediated ER-α suppression is important for regulation of MTOC as well as drug resistance.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Department of Integrated Biological Science, graduated school, Pusan National University, Busan, Republic of Korea.
authors.forename: Youn-Sang
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Molecular Biology, College of Natural Science, Department of Integrated Biological Science, graduated school, Pusan National University, Busan, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Chun
authors.affiliation: Department of Molecular Biology, College of Natural Science, Department of Integrated Biological Science, graduated school, Pusan National University, Busan, Republic of Korea.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Yoon
authors.affiliation: Department of Molecular Biology, College of Natural Science, Department of Integrated Biological Science, graduated school, Pusan National University, Busan, Republic of Korea. Electronic address: bjpark1219@pusan.ac.kr.
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D019313:BRCA1 Protein / Q000378:metabolism*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D000077267:Fulvestrant; D005822:Genetic Vectors; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D022101:Microtubule-Organizing Center / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000378:metabolism*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D014404:Tubulin; D050257:Tubulin Modulators; D000077267:Fulvestrant; D004958:Estradiol; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051135:Rad51 Recombinase; C497446:VHL protein, human; D017239:Paclitaxel