Abstract
It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear whether there are any innate surveillants that are able to ensure that keratinocytes undergo terminal differentiation, preventing the disease. IKKalpha induces keratinocyte terminal differentiation, and its downregulation promotes skin tumor development. However, its intrinsic function in skin cancer is unknown. Here, we found that mice with IKKalpha deletion in keratinocytes develop a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKalpha inhibits excessive mitosis, induces terminal differentiation, and prevents skin cancer through repressing an EGFR-driven autocrine loop. Thus, IKKalpha serves as an innate surveillant.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism
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Amphiregulin
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Animals
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Animals, Newborn
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EGF Family of Proteins
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Epidermal Growth Factor / genetics
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Epidermis / metabolism
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Epidermis / pathology
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression Regulation
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Glycoproteins / genetics
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Homeostasis*
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism*
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Intercellular Signaling Peptides and Proteins / genetics
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Keratinocytes / metabolism
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Keratinocytes / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, Knockout
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Mice, Transgenic
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Proto-Oncogene Proteins p21(ras) / metabolism
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism
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Skin / metabolism*
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Skin / pathology
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Skin Neoplasms / metabolism*
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Skin Neoplasms / pathology
Substances
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Amphiregulin
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Areg protein, mouse
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EGF Family of Proteins
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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Receptors, Tumor Necrosis Factor
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Epidermal Growth Factor
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ErbB Receptors
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Chuk protein, mouse
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I-kappa B Kinase
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Extracellular Signal-Regulated MAP Kinases
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ADAM Proteins
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Proto-Oncogene Proteins p21(ras)