IKKα Is Required to Maintain Skin Homeostasis and Prevent Skin Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE12111 | GEO | 2009/07/14
SECONDARY ACCESSION(S): PRJNA113807
REPOSITORIES: GEO
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Project description: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, however, whether there are any innate surveillants that ensure keratinocytes undergoing terminal differentiation, preventing the disease. IKKα induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its nature function in skin cancer is unknown. Here we found that mice with IKKα deletion in keratinocytes or in hair follicle keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKα inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKα serves as an innate surveillant. Experiment Overall Design: The differences in gene expression profiles of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes were analyzed using two dual-channel agilent microarrays in duplicates.
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Project description:ADAM17 and EGFR are essential key players for epidermal integrity. Keratinocyte-specific deletion of ADAM17 in mice results in pronounced alterations in terminal differentiation of keratinocytes leading to severe epidermal barrier defects with enhanced transepidermal water loss. Thereby, mice deficient for ADAM17 in keratinocytes phenocopy mice with a keratinocyte-specific deletion of EGFR, highlighting the role of ADAM17 as a “ligand sheddase”, as it sheds membrane bound EGFR ligands from the cell surface and finally modulates EGFR signaling. In this study we aim for the first proteomic / degradomic approach to characterize the disruption of the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation. Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17 and EGFR deficiency. These include massive proteome alterations of structural and regulatory components important for barrier formation, like transglutaminases, involucrin, S100 protein family members and S100 fused-type proteins, such as filaggrin, filaggrin-2 and hornerin. Cleavage site analysis using TAILS reveals, among other ADAM17 dependent cleavage sites, increased proteolytic processing of S100 fused-type proteins, including filaggrin-2. Alterations in proteolytic processing are supported by altered protein abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion, among them kallikreins, cathepsins and their inhibitors. In addition, N-terminal proteomics indicated usage of alternative translation start sites. This study highlights the essential role of proteolytic processing for maintenance of a functional epidermal barrier. Furthermore it suggests that most defects in formation of the postnatal epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR.
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Project description:Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are still poorly understood. We have previously demostrated that a dominante mutation in ZNF750 leads to a clinical phenotype that reminiscent of psoriasis and seborrehic dermatitis. We defined ZNF750 as a nuclear effector that is atrongly activated in and essiential for keratinocyte terminal differentiation. ZNF750 knockdown in HaCaT keratinocytes markedly reduced the expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, ZNF750 over-expression in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differnetiation, and with its downstream targets can serve in future elucidation of therapeutics for common disease of skin barrier Gene expression analysis: To determine the differentaition signature for HaCaT keratinocytes, with ZNF750 gene silencing, total RNA was isolated in biologic triplicates from cells induced to differentiate for twelve days and hybridized to Affymerix Human Gene 1.0 ST arrays.
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Project description:Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are still poorly understood. We have previously demonstrated that a dominant mutation in ZNF750 leads to a clinical phenotype that reminiscent of psoriasis and seborrheic dermatitis. We defined ZNF750 as a nuclear effector that is strongly activated in and essential for keratinocyte terminal differentiation. ZNF750 knockdown in HaCaT keratinocytes markedly reduced the expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, ZNF750 over-expression in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differentiation, and with its downstream targets can serve in future elucidation of therapeutics for common disease of skin barrier
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Project description:IKKα signaling in the nucleus or cytoplasm of keratinocytes leads to opposite skin phenotypes.
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