Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells

Yuri Kusano, Shunsuke Horie, Takahiro Shibata, Hideo Satsu, Makoto Shimizu, Eri Hitomi, Motohiro Nishida, Hitoshi Kurose, Ken Itoh, Akira Kobayashi, Masayuki Yamamoto, Koji Uchida

研究成果: ジャーナルへの寄稿記事

12 引用 (Scopus)

抄録

Kelch-like ECH-associated protein 1 (Keap1), a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex, regulates the induction of the phase 2 enzymes, such as glutathione S-transferase (GST), by repressing the transcription factor Nrf2. It is known that, in the human gastrointestinal tract, both GST A1 and P1 are constitutively expressed as the major GST isozymes. In the present study, using the Keap1-overexpressing derivatives of Caco-2 cells, human carcinoma cell line of colonic origin, by stable transfection of wild type Keap1, we investigated the molecular mechanism underlying the constitutive expression of these GST isozymes during differentiation. It was revealed that the overexpression of Keap1 completely repressed the constitutive expression of GST A1, but not GST P1. In Keap1-overexpressed cells, dome formation disappeared, and the formation of the intact actin cytoskeletal organization at cell-cell contact sites and the recruitment of E-cadherin and β-catenin to adherens junctions were inhibited. The constitutive GST A1 expression in Caco-2 cells was repressed by disruption of E-cadherin-mediated cell-cell adhesion, suggesting the correlation between epithelial cell polarization and induction of the basal GST A1 expressions during Caco-2 differentiation. Keap1 overexpression indeed inhibited the activation of the small guanosine triphosphatase Rac1 on the formation of E-cadherin-mediated cell-cell adhesion. The transfection of V12Rac1, the constitutively active Rac1 mutant, into Keap1-overexpressed cells promoted the basal GST A1 expression, suggesting that Keap1 regulated the basal GST Al1 expression during Caco-2 differentiation via Rac1 activation on the formation of E-cadherin-mediated cell-cell adhesion. The results of this study suggest the involvement of a novel Keap1-dependent signaling pathway for the induction of the constitutive GST A1 expression during epithelial cell differentiation.

元の言語英語
ページ(範囲)6169-6177
ページ数9
ジャーナルBiochemistry
47
発行部数23
DOI
出版物ステータス出版済み - 6 10 2008

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Caco-2 Cells
Glutathione Transferase
Proteins
Cadherins
Cell adhesion
Cell Adhesion
Cells
Isoenzymes
Transfection
Kelch-Like ECH-Associated Protein 1
Epithelial Cells
Chemical activation
Adherens Junctions
Catenins
Guanosine
Domes
Ligases
Ubiquitin
Gastrointestinal Tract
Actins

All Science Journal Classification (ASJC) codes

  • Biochemistry

これを引用

Kusano, Y., Horie, S., Shibata, T., Satsu, H., Shimizu, M., Hitomi, E., ... Uchida, K. (2008). Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells. Biochemistry, 47(23), 6169-6177. https://doi.org/10.1021/bi800199z

Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells. / Kusano, Yuri; Horie, Shunsuke; Shibata, Takahiro; Satsu, Hideo; Shimizu, Makoto; Hitomi, Eri; Nishida, Motohiro; Kurose, Hitoshi; Itoh, Ken; Kobayashi, Akira; Yamamoto, Masayuki; Uchida, Koji.

:: Biochemistry, 巻 47, 番号 23, 10.06.2008, p. 6169-6177.

研究成果: ジャーナルへの寄稿記事

Kusano, Y, Horie, S, Shibata, T, Satsu, H, Shimizu, M, Hitomi, E, Nishida, M, Kurose, H, Itoh, K, Kobayashi, A, Yamamoto, M & Uchida, K 2008, 'Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells', Biochemistry, 巻. 47, 番号 23, pp. 6169-6177. https://doi.org/10.1021/bi800199z
Kusano Y, Horie S, Shibata T, Satsu H, Shimizu M, Hitomi E その他. Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells. Biochemistry. 2008 6 10;47(23):6169-6177. https://doi.org/10.1021/bi800199z
Kusano, Yuri ; Horie, Shunsuke ; Shibata, Takahiro ; Satsu, Hideo ; Shimizu, Makoto ; Hitomi, Eri ; Nishida, Motohiro ; Kurose, Hitoshi ; Itoh, Ken ; Kobayashi, Akira ; Yamamoto, Masayuki ; Uchida, Koji. / Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells. :: Biochemistry. 2008 ; 巻 47, 番号 23. pp. 6169-6177.
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abstract = "Kelch-like ECH-associated protein 1 (Keap1), a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex, regulates the induction of the phase 2 enzymes, such as glutathione S-transferase (GST), by repressing the transcription factor Nrf2. It is known that, in the human gastrointestinal tract, both GST A1 and P1 are constitutively expressed as the major GST isozymes. In the present study, using the Keap1-overexpressing derivatives of Caco-2 cells, human carcinoma cell line of colonic origin, by stable transfection of wild type Keap1, we investigated the molecular mechanism underlying the constitutive expression of these GST isozymes during differentiation. It was revealed that the overexpression of Keap1 completely repressed the constitutive expression of GST A1, but not GST P1. In Keap1-overexpressed cells, dome formation disappeared, and the formation of the intact actin cytoskeletal organization at cell-cell contact sites and the recruitment of E-cadherin and β-catenin to adherens junctions were inhibited. The constitutive GST A1 expression in Caco-2 cells was repressed by disruption of E-cadherin-mediated cell-cell adhesion, suggesting the correlation between epithelial cell polarization and induction of the basal GST A1 expressions during Caco-2 differentiation. Keap1 overexpression indeed inhibited the activation of the small guanosine triphosphatase Rac1 on the formation of E-cadherin-mediated cell-cell adhesion. The transfection of V12Rac1, the constitutively active Rac1 mutant, into Keap1-overexpressed cells promoted the basal GST A1 expression, suggesting that Keap1 regulated the basal GST Al1 expression during Caco-2 differentiation via Rac1 activation on the formation of E-cadherin-mediated cell-cell adhesion. The results of this study suggest the involvement of a novel Keap1-dependent signaling pathway for the induction of the constitutive GST A1 expression during epithelial cell differentiation.",
author = "Yuri Kusano and Shunsuke Horie and Takahiro Shibata and Hideo Satsu and Makoto Shimizu and Eri Hitomi and Motohiro Nishida and Hitoshi Kurose and Ken Itoh and Akira Kobayashi and Masayuki Yamamoto and Koji Uchida",
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T1 - Keap1 regulates the constitutive expression of GST A1 during differentiation of caco-2 cells

AU - Kusano, Yuri

AU - Horie, Shunsuke

AU - Shibata, Takahiro

AU - Satsu, Hideo

AU - Shimizu, Makoto

AU - Hitomi, Eri

AU - Nishida, Motohiro

AU - Kurose, Hitoshi

AU - Itoh, Ken

AU - Kobayashi, Akira

AU - Yamamoto, Masayuki

AU - Uchida, Koji

PY - 2008/6/10

Y1 - 2008/6/10

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AB - Kelch-like ECH-associated protein 1 (Keap1), a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex, regulates the induction of the phase 2 enzymes, such as glutathione S-transferase (GST), by repressing the transcription factor Nrf2. It is known that, in the human gastrointestinal tract, both GST A1 and P1 are constitutively expressed as the major GST isozymes. In the present study, using the Keap1-overexpressing derivatives of Caco-2 cells, human carcinoma cell line of colonic origin, by stable transfection of wild type Keap1, we investigated the molecular mechanism underlying the constitutive expression of these GST isozymes during differentiation. It was revealed that the overexpression of Keap1 completely repressed the constitutive expression of GST A1, but not GST P1. In Keap1-overexpressed cells, dome formation disappeared, and the formation of the intact actin cytoskeletal organization at cell-cell contact sites and the recruitment of E-cadherin and β-catenin to adherens junctions were inhibited. The constitutive GST A1 expression in Caco-2 cells was repressed by disruption of E-cadherin-mediated cell-cell adhesion, suggesting the correlation between epithelial cell polarization and induction of the basal GST A1 expressions during Caco-2 differentiation. Keap1 overexpression indeed inhibited the activation of the small guanosine triphosphatase Rac1 on the formation of E-cadherin-mediated cell-cell adhesion. The transfection of V12Rac1, the constitutively active Rac1 mutant, into Keap1-overexpressed cells promoted the basal GST A1 expression, suggesting that Keap1 regulated the basal GST Al1 expression during Caco-2 differentiation via Rac1 activation on the formation of E-cadherin-mediated cell-cell adhesion. The results of this study suggest the involvement of a novel Keap1-dependent signaling pathway for the induction of the constitutive GST A1 expression during epithelial cell differentiation.

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