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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cell Proliferation
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / physiology
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DNA-Binding Proteins / metabolism
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ErbB Receptors / biosynthesis
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ErbB Receptors / genetics
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Genes, Tumor Suppressor
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Homeodomain Proteins / metabolism
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Humans
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Interferon Regulatory Factors / biosynthesis
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism*
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Keratinocytes / physiology*
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Oncogene Protein p21(ras) / metabolism
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Transcription Factor HES-1
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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HEY1 protein, human
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Homeodomain Proteins
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IRF6 protein, human
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Interferon Regulatory Factors
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NOTCH1 protein, human
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RNA, Small Interfering
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Receptor, Notch1
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Transcription Factor HES-1
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HES1 protein, human
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ErbB Receptors
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Oncogene Protein p21(ras)