The overall goal of my research is to identify and characterize genetic factors leading to tumor development in human by establishing mouse models for development of anticancer drugs. The objective of the present study is to understand the function of ubiquitin ligation enzymes and deubiquitin enzymes during progression of different human skin cancers. This is analysed by generating transgenic animals and applying tumour-promoting protocol to specifically dissect the role of these enzymes during progression of cancer on mouse skin. During the proposed studies, mice deficient in various ubiquitin mediated signaling molecules such as CYLD and Bcl-3 will be used to test their contribution to cancer development. In addition we will identify novel E3 ligation and deubiquitination enzymes involved in progression of skin cancer using a multidisciplinary approach that combines mouse genetic, masspectrometry in vivo and gene expression profiling. To correlate information obtained from animal model to the development of treatments of human cancer, we are generating human tissue platforms from skin cancer patients regenerated on immune deficient mice. This model enables to study human epithelial neoplasms under in situ conditions. The results obtained in the transgenic animals as well as human tissue platform are correlated and compared to the samples from melanoma and non-melanoma human cancer patients. Furthermore, transgenic animals and transplanted human tissues are treated with proposed drug before tumor induction to test their specificity. Using state-of-the-art approaches and techniques, this project will identify novel markers for improved diagnosis and validation of candidate drug target for skin cancer therapies.