Beta defensin 3: UV induction and effects on melaocyte genome stability

We are interested in defining cellular and molecular signaling events in the skin that influence melanoma risk. We focus on the melanocortin-1 receptor (MC1R) signaling axis which is intricately involved in adaptive melanization (tanning) and melanocytic recovery from UV damage. Loss-of-function polymorphisms of MC1R signaling strongly correlate with a fair skin complexion, a tendency to burn rather than tan following UV exposure and up to a four-fold enhanced lifetime melanoma risk. It is essential to understand how UV impacts melanocyte physiology since the overwhelming majority of mutations found in melanoma are directly caused by UV damage to DNA. The MC1R, expressed on melanocytes, interacts with a variety of paracrine factors produced by keratinocytes and other cells, most notably á-melanocyte stimulating hormone (MSH), the high-affinity activating agonist of MC1R. Signaling by MC1R, however, is complex and is also influenced by other factors including â-defensin 3 (BD3), a recently described MC1R ligand made by keratinocytes in response to infectious and inflammatory agents. We confirm robust BD3 expression in keratinocytes after UV radiation and hypothesize that BD3 impacts melanocyte MC1R signaling and UV responses through paracrine interactions with melanocytes. Accordingly, we propose to determine the molecular mechanisms regulating epidermal keratinocyte BD3 production and to define functional consequences of BD3 exposure in melanocytes focusing on repair of UV damage. We will determine the roles of well-characterized cellular stress response pathways in UV-induced BD3 production by keratinocytes and identify regulatory genetic elements that control UV-induced its transcriptional regulation. We will also determine the physiologic consequences of BD3 exposure on melanocyte UV DNA repair responses known to be MC1R-dependent and critical for UV resistance. Together, these studies will clarify the importance of keratinocyte-derived BD3 in UV resistance and will serve as a platform for rational UV-preventive strategies through selective manipulation of adaptive UV responses in the skin.