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タイトル: Decreased responsiveness of naturally occurring mutants of human estrogen receptor α to estrogens and antiestrogens
著者: Komagata, Sayaka
Nakajima, Miki link image link image
Tsuchiya, Yuki
Kato, Miki
Kizu, Ryoichi link image
Kyo, Satoru link image
Yokoi, Tsuyoshi link image
中嶋, 美紀
加藤, 美紀
京, 哲
横井, 毅
発行日: 2006年 7月
出版社(者): Elsevier
引用: Journal of Steroid Biochemistry and Molecular Biology, 100 (1-3), pp. 79-86
雑誌名: Journal of Steroid Biochemistry and Molecular Biology
ISSN: 0960-0760
巻: 100
号: 1-3
開始ページ: 79
終了ページ: 86
キーワード: Antiestrogens
Estradiol
Estrogen receptor
Mutation
Transcriptional activity
抄録: Estrogen receptor α (ERα) is a ligand-inducible transcription factor that mediates the biological effects of estrogens and antiestrogens. Many point mutations in the human ERα gene have been reported to be associated with breast cancer, endometrial cancer, and psychiatric diseases. However, functional analyses for most mutants with amino acid changes are still lacking. In the present study, to investigate the effects of point mutations on the function, gel-shift assays and luciferase assays were performed for eight kinds of mutated ERα proteins, including a single nucleotide change of C207G (N69K), G478T (G160C), T887C (L296P), A908G (K303R), C926T (S309F), A1058T (E353V), A1186G (M396V), and G1231deletion (411fsX7). The mutated ERα expression plasmids were constructed by site-directed mutagenesis. With gel-shift assays using in vitro translated ERα proteins, binding to the consensus estrogen response element (ERE) was observed for the mutated ERα proteins except ERα (G160C) and ERα (411fsX7), the binding of which was comparable with that of the wild type. Western blot analyses showed that ERα (G160C) could not be efficiently translated with the in vitro transcription/translation system and that ERα (411fsX7) produced a truncated protein. To investigate the transactivation potency, wild-type or mutated ERα expression plasmids were co-transfected with pGL3-3EREc38 reporter plasmid into human breast adenocarcinoma MDA-MB-435 cells. The concentration-response curves (10 pM-100 nM E2) of the mutant ERα proteins except ERα (E353V) and ERα (411fsX7) were similar to that of wild-type ERα. However, at a low level of E2 (100 pM), the mutants ERα (N69K), ERα (L296P), ERα (S309F), and ERα (M396V) showed a significant decrease of transactivation compared with that of the wild-type ERα. The mutants ERα (E353V) and ERα (411fsX7) did not show responsiveness to E2 and antiestrogens, 4-hydroxytamoxifen (4OHT) and ICI 182,780. The mutant ERα (S309F) showed decreased responsiveness for the antiestrogenicity of 4OHT. In conclusion, we found that some of the naturally occurring human ERα mutants with amino acid changes may have an altered responsiveness to estrogen and antiestrogens. © 2006 Elsevier Ltd. All rights reserved.
URI: http://hdl.handle.net/2297/2803
関連URI: http://www.elsevier.com/locate/issn/09600760
http://dx.doi.org/10.1016/j.clpt.2006.05.012
資料種別: Journal Article
版表示: author
出現コレクション:1. 査読済論文(医学・保健)

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