Fuctinonal analysis of cancer related genes by targeted mutagenesis in mice

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In this project, using technologies of mouse reverse genetics including a conditional gene targeting in mice, we have performed functional analyses on many cancer-related genes, such as tumor suppressor genes and oncogenes. Especially, functions of cancer related genes involved in Wnt, Sonic Hedgehog and PIP3 signaling pathways were intensely analyzed. Through these studies, we have succeeded to show substantial amount of evidence for molecular mechanisms regulating the process of carcinogenesis in vivo. In addition, we have also succeeded in establishing several ideal models `for human carcinogenesis : For example, we could clearly show that the inactivation of Patched-1 in outer germinal layer cells of developing cerebellum may suppress their growth arrest resulting in the formation of medulloblastoma in cerebellum. We could also show that Pten may actually function as a negative regulator of PiP3 pathway in varied tissues in mice, such as T cells, keratinocytes, hepatocytes and epithelias cells of prostate, and Pten inactivation actually induced tumors in these tissues. These information may greatly contribute for elucidation of molecular mechanisms of human carcinogenesis.