Restivo, GaetanaBach-Cuc, NguyenDziunycz, PiotrRistorcelli, ElodieRyan, Russell J. H.Oezuysal, Oezden YalcinDi Piazza, MatteoRadtke, FreddyDixon, Michael J.Hofbauer, Guenther F. L.Lefort, KarineDotto, Paolo G.2012-06-122012-06-122012-06-12201110.1038/emboj.2011.325https://infoscience.epfl.ch/handle/20.500.14299/81600WOS:000297691500006While 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. The EMBO Journal (2011) 30, 4571-4585. doi:10.1038/emboj.2011.325; Published online 9 September 2011 Subject Categories: signal transduction; molecular biology of diseasekeratinocytesNotchp63squamous cell carcinomatumour suppressionInterferon Regulatory Factor-6Nf-Kappa-BEpidermal DifferentiationTranscription FactorsSignaling PathwayStem-CellsP63SkinCancerActivationtext::journal::journal article::research article