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

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 ...

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interacts with poly-ubiquitinated proteins and is essential for the degradation of IκBα to activate NFκB. We show that vesnarinone binding to VCP impairs the degradation of IκBα and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of poly-ubiquitinated IκBα, resulting in the suppression of TNFα mRNA expression.

Date: Feb. 07, 2013

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