title: Vesnarinone suppresses TNFα mRNA expression by inhibiting valosin-containing protein.
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 IκBα to activate nuclear factor (NF)κB. We show that vesnarinone 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 by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression.
authors: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.
authors: Kentaro
authors: K
authors: Hotta
authors: Akihiro
authors: A
authors: Nashimoto
authors: Eiji
authors: E
authors: Yasumura
authors: Masafumi
authors: M
authors: Suzuki
authors: Motoki
authors: M
authors: Azuma
authors: Yosuke
authors: Y
authors: Iizumi
authors: Daisuke
authors: D
authors: Shima
authors: Ryusuke
authors: R
authors: Nabeshima
authors: Masaki
authors: M
authors: Hiramoto
authors: Akira
authors: A
authors: Okada
authors: Kumiko
authors: K
authors: Sakata-Sogawa
authors: Makio
authors: M
authors: Tokunaga
authors: Takumi
authors: T
authors: Ito
authors: Hideki
authors: H
authors: Ando
authors: Satoshi
authors: S
authors: Sakamoto
authors: Yasuaki
authors: Y
authors: Kabe
authors: Shinichi
authors: S
authors: Aizawa
authors: Takeshi
authors: T
authors: Imai
authors: Yuki
authors: Y
authors: Yamaguchi
authors: Hajime
authors: H
authors: Watanabe
authors: Hiroshi
authors: H
authors: Handa
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011719:Pyrazines; D011804:Quinolines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C041667:vesnarinone; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein