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IRF6 is a mediator of Notch pro‐differentiation and tumour suppressive function in keratinocytes
Author(s) -
Restivo Gaetana,
Nguyen BachCuc,
Dziunycz Piotr,
Ristorcelli Elodie,
Ryan Russell J H,
Özuysal Özden Yalçin,
Di Piazza Matteo,
Radtke Freddy,
Dixon Michael J,
Hofbauer Günther F L,
Lefort Karine,
Dotto G Paolo
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.325
Subject(s) - biology , mediator , function (biology) , microbiology and biotechnology , notch signaling pathway , cancer research , signal transduction
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.