Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein

Shu Takahashi; Hideki Wakui; Jan Åke Gustafsson; Johanna Zilliacus; Hideaki Itoh

doi:10.1006/bbrc.2000.3104

Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein

Shu Takahashi, Hideki Wakui, Jan Åke Gustafsson, Johanna Zilliacus, Hideaki Itoh

Research Institute

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive activity. MIZ has been approved in Japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nephritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins involved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor. We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3 η dose dependently in vitro. MIZ also has a stimulatory effect on transcriptional activation by the GR. Our results point to the possibility that one mechanism for the therapeutic effect of MIZ could be to regulate the GR function via 14-3-3 proteins. (C) 2000 Academic Press.

Original language	English (US)
Pages (from-to)	87-92
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	274
Issue number	1
DOIs	https://doi.org/10.1006/bbrc.2000.3104
State	Published - Jul 21 2000

Keywords

14-3-3
Glucocorticoid receptor
Immunosuppression
Mizoribine
Nuclear receptor
Transactivation

ASJC Scopus subject areas

Biochemistry
Biophysics
Molecular Biology

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10.1006/bbrc.2000.3104

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title = "Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein",

abstract = "Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive activity. MIZ has been approved in Japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nephritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins involved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor. We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3 η dose dependently in vitro. MIZ also has a stimulatory effect on transcriptional activation by the GR. Our results point to the possibility that one mechanism for the therapeutic effect of MIZ could be to regulate the GR function via 14-3-3 proteins. (C) 2000 Academic Press.",

keywords = "14-3-3, Glucocorticoid receptor, Immunosuppression, Mizoribine, Nuclear receptor, Transactivation",

author = "Shu Takahashi and Hideki Wakui and Gustafsson, {Jan {\AA}ke} and Johanna Zilliacus and Hideaki Itoh",

note = "Funding Information: This work was supported by grants from the Swedish Medical Research Council (12557), {\AA}ke Wiberg Foundation, Lars Hierta Foundation, and Emil and Wera Cornell Foundation and in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (11671024). Johannna Zilliacus was supported by a junior research position from the Swedish Research Council.",

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AU - Takahashi, Shu

AU - Wakui, Hideki

AU - Gustafsson, Jan Åke

AU - Zilliacus, Johanna

AU - Itoh, Hideaki

N1 - Funding Information: This work was supported by grants from the Swedish Medical Research Council (12557), Åke Wiberg Foundation, Lars Hierta Foundation, and Emil and Wera Cornell Foundation and in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (11671024). Johannna Zilliacus was supported by a junior research position from the Swedish Research Council.

PY - 2000/7/21

Y1 - 2000/7/21

N2 - Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive activity. MIZ has been approved in Japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nephritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins involved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor. We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3 η dose dependently in vitro. MIZ also has a stimulatory effect on transcriptional activation by the GR. Our results point to the possibility that one mechanism for the therapeutic effect of MIZ could be to regulate the GR function via 14-3-3 proteins. (C) 2000 Academic Press.

AB - Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive activity. MIZ has been approved in Japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nephritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins involved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor. We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3 η dose dependently in vitro. MIZ also has a stimulatory effect on transcriptional activation by the GR. Our results point to the possibility that one mechanism for the therapeutic effect of MIZ could be to regulate the GR function via 14-3-3 proteins. (C) 2000 Academic Press.

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KW - Transactivation

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Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein

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