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Int J Biochem Cell Biol. 2011 Nov;43(11):1612-20. doi: 10.1016/j.biocel.2011.07.010. Epub 2011 Jul 26.

AWP1 binds to tumor necrosis factor receptor-associated factor 2 (TRAF2) and is involved in TRAF2-mediated nuclear factor-kappaB signaling.

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1
Department of Medicine, Graduate School, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. ejchang@amc.seoul.kr

Abstract

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an adaptor protein which involves in the activation of the transcription factor, nuclear factor kappaB (NF-κB), in the tumor necrosis factor (TNF) receptor pathway. This signaling is modulated by proteins that interact with tumor necrosis factor receptor-associated factor 2. In this study, we identified the zinc-finger protein AWP1 as a tumor necrosis factor receptor-associated factor 2-interacting protein through yeast two-hybrid screening. We found that AWP1 directly interacted with the C-terminal tumor necrosis factor receptor-associated factor (TRAF) domain of tumor necrosis factor receptor-associated factor 2. Knockdown of AWP1 using small hairpin RNA significantly decreased nuclear factor kappaB activity but increased tumor necrosis factor alpha (TNFα)-induced apoptosis, presumably by decreasing the induction of nuclear factor kappaB-responsive anti-apoptotic molecules, including FICE-like inhibitory protein (FLIP), X-linked inhibitor of apoptosis protein (XIAP), Bcl-2, and Bcl-xL. In contrast, overexpression of wild-type AWP1 inhibited nuclear factor kappaB activation. Detailed domain mapping experiments showed that the AN1 domain of AWP1 mediated the functional interaction with tumor necrosis factor receptor-associated factor 2, and the A20 domain was responsible for the negative regulation of nuclear factor kappaB activation. Importantly, ectopic AWP1 overexpression led to an A20 domain-dependent increase in K-48 ubiquitination of tumor necrosis factor receptor-associated factor 2. These data indicate that AWP1 binds to tumor necrosis factor receptor-associated factor 2 and that regulates tumor necrosis factor alpha-induced nuclear factor kappaB activation through two distinct domains.

PMID:
21810480
DOI:
10.1016/j.biocel.2011.07.010
[Indexed for MEDLINE]
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