title: Critical role for constitutive type I interferon signaling in the prevention of cellular transformation.
abstract: Interferons-alpha/beta, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN-alpha/beta show a preventive role in cellular transformation. Ifnar1-deficient (Ifnar1(-/-)) MEF, which are devoid of IFN-alpha/beta signal, undergo a spontaneous transformation during long-term cell culture. Similar to Irf1(-/-) MEF, primary Ifnar1(-/-) MEF become tumorigenic in nude mice by the expression of activated c-Ha-Ras oncoprotein. However, Ifnar1(-/-) MEF do not show any abnormal growth properties. A similar observation is made in Ifnb(-/-) MEF that fail to produce constitutive IFN-alpha/beta, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1(-/-) mice develop chemically-induced skin papilloma more severely than wild-type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell-intrinsic role of the weak signal by constitutively produced IFN-alpha/beta to prevent cells from transformation, which may be mediated by a hitherto-unknown pathway(s) downstream of the IFN-alpha/beta receptor.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Chen
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Mitani
authors.forename: Eri
authors.initials: E
authors.lastname: Oda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozawa
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Chen
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Myoung Kwon
authors.initials: MK
authors.lastname: Choi
authors.forename: Toshiroh
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics
chemical_list: D002273:Carcinogens; C507964:IFNAR1 protein, human; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta