title: IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes.
abstract: While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch-dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation-related genes, while it is not required for induction of 'canonical' Notch targets like p21(WAF1/Cip1), Hes1 and Hey1. Down-modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo, promoting ras-induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression.
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Gaetana
authors: G
authors: Restivo
authors: Bach-Cuc
authors: BC
authors: Nguyen
authors: Piotr
authors: P
authors: Dziunycz
authors: Elodie
authors: E
authors: Ristorcelli
authors: Russell J H
authors: RJ
authors: Ryan
authors: Özden Yalçin
authors: ÖY
authors: Özuysal
authors: Matteo
authors: M
authors: Di Piazza
authors: Freddy
authors: F
authors: Radtke
authors: Michael J
authors: MJ
authors: Dixon
authors: Günther F L
authors: GF
authors: Hofbauer
authors: Karine
authors: K
authors: Lefort
authors: G Paolo
authors: GP
authors: Dotto
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D018398:Homeodomain Proteins; D050835:Interferon Regulatory Factors; D015689:Oncogene Protein p21(ras); D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C485631:HEY1 protein, human; C109803:IRF6 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human