2013 Fiscal Year Final Research Report

Development of regulators of the LUBAC ubiquitin ligase that modulate NF-kappaB activation

Research Project

Project/Area Number	24659136
Research Category	Grant-in-Aid for Challenging Exploratory Research
Allocation Type	Single-year Grants
Research Field	General medical chemistry
Research Institution	Kyoto University
Principal Investigator	IWAI Kazuhiro 京都大学, 医学(系)研究科(研究院), 教授 (60252459)
Project Period (FY)	2012-04-01 – 2014-03-31
Keywords	細胞内シグナル伝達
Research Abstract	NF-kappaB is a family of a transcription factor that involves in various biologcal phenomena including inflammation, immune responses, and cell survival. Abnormal activation NF-kappaB is also known to be related to the pathogenesis of various diseases. Thus, regulation of NF-kappaB is a suitable target of drugs for those diseases. Since we have identified LUBAC-mediated linear polyubiquitination is involved in NF-kappaB activation, we tried to develop the agents that up-regulate or inhibit LUBAC's ligase activity. We then identified a small chemical that inhibits LUBAC-mediated linear polyubiquitination and NF-kappaB actvation. Also, we found that interferon-gamma increases the amount of LUBAC and enhances NF-kappaB actvation.