Article: article from journal or magazin.
IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes.
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.
Animals, Basic Helix-Loop-Helix Transcription Factors/metabolism, Cell Cycle Proteins/metabolism, Cell Differentiation, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21/metabolism, Cyclin-Dependent Kinase Inhibitor p21/physiology, DNA-Binding Proteins/metabolism, Genes, Tumor Suppressor, Homeodomain Proteins/metabolism, Humans, Interferon Regulatory Factors/biosynthesis, Interferon Regulatory Factors/genetics, Keratinocytes/cytology, Keratinocytes/metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Oncogene Protein p21(ras)/metabolism, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Receptor, Epidermal Growth Factor/biosynthesis, Receptor, Epidermal Growth Factor/genetics, Receptor, Notch1/genetics, Receptor, Notch1/metabolism, Signal Transduction, Skin Neoplasms/metabolism, Skin Neoplasms/pathology
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