Vesnarinone suppresses TNFa mRNA expression by inhibiting valosin-containing protein

Kentaro Hotta; Akihiro Nashimoto; Eiji Yasumura; Masafumi Suzuki; Motoki Azuma; Yosuke Iizumi; Daisuke Shima; Ryusuke Nabeshima; Masaki Hiramoto; Akira Okada; Kumiko Sakata-Sogawa; Makio Tokunaga; Takumi Ito; Hideki Ando; Satoshi Sakamoto; Yasuaki Kabe; Shinichi Aizawa; Takeshi Imai; Yuki Yamaguchi; Hajime Watanabe; Hiroshi Handa

doi:10.1124/mol.112.081935

Vesnarinone suppresses TNFa mRNA expression by inhibiting valosin-containing protein

Kentaro Hotta, Akihiro Nashimoto, Eiji Yasumura, Masafumi Suzuki, Motoki Azuma, Yosuke Iizumi, Daisuke Shima, Ryusuke Nabeshima, Masaki Hiramoto, Akira Okada, Kumiko Sakata-Sogawa, Makio Tokunaga, Takumi Ito, Hideki Ando, Satoshi Sakamoto, Yasuaki Kabe, Shinichi Aizawa, Takeshi Imai, Yuki Yamaguchi, Hajime WatanabeHiroshi Handa

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

8 Citations (Scopus)

Abstract

Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IkBa to activate nuclear factor (NF)kB. We show that vesnarinone impairs the degradation of IkBa, and that the impairment of the degradation of IkBa is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFkB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IkBa, resulting in the suppression of tumor necrosis factor-a mRNA expression.

Original language	English
Pages (from-to)	930-938
Number of pages	9
Journal	Molecular Pharmacology
Volume	83
Issue number	5
DOIs	https://doi.org/10.1124/mol.112.081935
Publication status	Published - 2013 May
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1124/mol.112.081935

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Hotta, K., Nashimoto, A., Yasumura, E., Suzuki, M., Azuma, M., Iizumi, Y., Shima, D., Nabeshima, R., Hiramoto, M., Okada, A., Sakata-Sogawa, K., Tokunaga, M., Ito, T., Ando, H., Sakamoto, S., Kabe, Y., Aizawa, S., Imai, T., Yamaguchi, Y., ... Handa, H. (2013). Vesnarinone suppresses TNFa mRNA expression by inhibiting valosin-containing protein. Molecular Pharmacology, 83(5), 930-938. https://doi.org/10.1124/mol.112.081935

Hotta, K, Nashimoto, A, Yasumura, E, Suzuki, M, Azuma, M, Iizumi, Y, Shima, D, Nabeshima, R, Hiramoto, M, Okada, A, Sakata-Sogawa, K, Tokunaga, M, Ito, T, Ando, H, Sakamoto, S, Kabe, Y, Aizawa, S, Imai, T, Yamaguchi, Y, Watanabe, H & Handa, H 2013, 'Vesnarinone suppresses TNFa mRNA expression by inhibiting valosin-containing protein', Molecular Pharmacology, vol. 83, no. 5, pp. 930-938. https://doi.org/10.1124/mol.112.081935

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abstract = "Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IkBa to activate nuclear factor (NF)kB. We show that vesnarinone impairs the degradation of IkBa, and that the impairment of the degradation of IkBa is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFkB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IkBa, resulting in the suppression of tumor necrosis factor-a mRNA expression.",

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AU - Hotta, Kentaro

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AU - Azuma, Motoki

AU - Iizumi, Yosuke

AU - Shima, Daisuke

AU - Nabeshima, Ryusuke

AU - Hiramoto, Masaki

AU - Okada, Akira

AU - Sakata-Sogawa, Kumiko

AU - Tokunaga, Makio

AU - Ito, Takumi

AU - Ando, Hideki

AU - Sakamoto, Satoshi

AU - Kabe, Yasuaki

AU - Aizawa, Shinichi

AU - Imai, Takeshi

AU - Yamaguchi, Yuki

AU - Watanabe, Hajime

AU - Handa, Hiroshi

PY - 2013/5

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AB - Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IkBa to activate nuclear factor (NF)kB. We show that vesnarinone impairs the degradation of IkBa, and that the impairment of the degradation of IkBa is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFkB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IkBa, resulting in the suppression of tumor necrosis factor-a mRNA expression.

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Vesnarinone suppresses TNFa mRNA expression by inhibiting valosin-containing protein

Abstract

ASJC Scopus subject areas

UN SDGs

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