NF-kB in epidermal signal transduction and tumor development

Sammanfattning: The transcription factor NF-kappaB has been extensively studied since its discovery. NFkappaB has been shown to be invoved in many cellular processes in many different cell types. However, its functions in skin physiology and epidermal tumor development are largely unknown. In this thesis we have investigated signaling pathways leading to NF-kappaB activation in keratinocytes and studied the function of NF-kappaB in development and carcinogenesis of the skin. We demonstrate that ultraviolet (UV) radiation can act in keratinocytes via TNF receptor 1 and TRAF 2 to elicit Rel protein-DNA binding resulting in enhanced transcription. The signaling induced is ligand independent and is likely to be a major pathway for Rel/NF- kappaB activation by UVB in the skin. We selectively blocked Rel/NF-kappaB activation in the skin by targeted expression of a signal resistant form of IkappaB-alpha in the epidermis of transgenic mice. Our data demonstrate that selective inhibition of Rel/NF-kappaB signaling in epithelial skin cells disrupts normal epidermal homeostasis and hair follicle development, increases the number of keratinocytes undergoing apoptosis and leads to the development of squamous cell carcinoma. In a characterization of the progressive dysplasia leading to squamous cell carcinoma development we observed upregulation of the proinflammatory cytokine TNF-alpha in transgenic skin, associated with a mixed inflammatory cell infiltrate. Furthermore, we show that inhibition of NF-kappaB signaling in mouse skin generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by gamma-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Ha-ras or p53 gene, suggesting that inhibition of NFkappaB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. In summary, we have identified TNF receptor 1 as a transducer of the UV-signal in the activation of NF-kappaB. We have shown using a transgenic mouse model, that NF-kappaB plays an important part in epidermal proliferation and tumor development. The elucidation of the mechanisms responsible for the tumor development will provide important new knowledge in our understanding of skin carcinogenesis.