title: Ymer acts as a multifunctional regulator in nuclear factor-κB and Fas signaling pathways.
abstract: The nuclear factor (NF)-κB family of transcription factors regulates diverse cellular functions, including inflammation, oncogenesis and apoptosis. It was reported that A20 plays a critical role in the termination of NF-κB signaling after activation. Previously, we showed that Ymer interacts and collaborates with A20, followed by degradation of receptor-interacting protein (RIP) and attenuation of NF-κB signaling. Here we show the function of Ymer in regulation of several signaling pathways including NF-κB on the basis of results obtained by using Ymer transgenic (Ymer Tg) mice. Ymer Tg mice exhibited impaired immune responses, including NF-κB and mitogen-activated protein kinase (MAPK) activation, cell proliferation and cytokine production, to tumor necrosis factor (TNF)-α, polyI:C or lipopolysaccharide (LPS) stimulation. Ymer Tg mice were more resistant to LPS-induced septic shock than wild-type mice. Transgene of Ymer inhibited the onset of glomerulonephritis in lpr/lpr mice as an autoimmune disease model. In contrast to the inflammatory immune response to LPS, Fas-mediated cell death was strongly induced in liver cells of Ymer Tg mice in which Ymer is abundantly expressed. These findings suggest that Ymer acts as a regulator downstream of several receptors and that Ymer functions as a positive or negative regulator in a signaling pathway-dependent manner.
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Tadasuke
authors.initials: T
authors.lastname: Tsukiyama
authors.forename: Mayuko
authors.initials: M
authors.lastname: Matsuda-Tsukiyama
authors.forename: Miyuki
authors.initials: M
authors.lastname: Bohgaki
authors.forename: Sayuri
authors.initials: S
authors.lastname: Terai
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D060168:Thymocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C478972:CCDC50 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor