Role of Csn5 in Epidermal Homeostasis

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DESCRIPTION (provided by applicant): Amplification of 8q is one of the most common chromosomal abnormalities in human squamous cell carcinoma (SCC), but the oncogenes on 8q that drive these cancers have been unclear. Coordinate amplification of CSN5 on chromosome 8q13 with MYC on 8q24 has been recently shown to be a hallmark of human tumors with increased risk of metastasis and patient mortality. Moreover, CSN5 and MYC have been found to be required for epithelial transformation and progression. CSN5 inhibits the normal ultraviolet light- induced apoptotic response in the epidermis and also increases the transcriptional potency of MYC, suggesting multiple potential mechanisms for CSNS's promotion of carcinogenesis. In order to define the mechanism by which CSN5 cooperates with MYC to disrupt epidermal homeostasis and drive SCC, the aims of this proposal are to examine the role of CSN5 in DMA damage response, epidermal differentiation and epidermal stem cell maintenance. CSN5 protease activity represents a potential therapeutic target of not only cancers, but also other proliferative and light-mediated disorders of the skin. This award will enable the principal investigator, a dermatology-trained physician-scientist, to receive intensive training in epithelial biology research and develop his own independent research program. He performed his graduate work in cancer biology and has completed his clinical training in dermatology. He has chosen to work in a laboratory to gain expertise with skin biology and in vivo mammalian model systems to prepare him to establish his own laboratory focusing on pathways that regulate sternness and carcinogenesis as well as the development of novel targeted therapeutics for skin disease. Stanford University is providing him with full institutional support, extensive resources, and opportunity for collaborations with experts in the field. He will be further trained in ethical conduct, experimental design, grantsmanship, and laboratory management to transition him to a full time academic position in translational medical research on a tenure track spending 90% of his time on research and 10% on clinical activities.