PT - JOURNAL ARTICLE AU - Kentaro Hotta AU - Akihiro Nashimoto AU - Eiji Yasumura AU - Masafumi Suzuki AU - Motoki Azuma AU - Yosuke Iizumi AU - Daisuke Shima AU - Ryusuke Nabeshima AU - Masaki Hiramoto AU - Akira Okada AU - Kumiko Sakata-Sogawa AU - Makio Tokunaga AU - Takumi Ito AU - Hideki Ando AU - Satoshi Sakamoto AU - Yasuaki Kabe AU - Shinichi Aizawa AU - Takeshi Imai AU - Yuki Yamaguchi AU - Hajime Watanabe AU - Hiroshi Handa TI - Vesnarinone Suppresses TNFα mRNA Expression by Inhibiting Valosin-containing Protein AID - 10.1124/mol.112.081935 DP - 2013 Jan 01 TA - Molecular Pharmacology PG - mol.112.081935 4099 - http://molpharm.aspetjournals.org/content/early/2013/02/07/mol.112.081935.short 4100 - http://molpharm.aspetjournals.org/content/early/2013/02/07/mol.112.081935.full 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 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.