Fuctinonal analysis of cancer related genes by targeted mutagenesis in mice

在本项目中，我们利用小鼠反向遗传学技术，包括小鼠条件基因打靶，对许多癌症相关基因，如肿瘤抑制基因和癌基因进行了功能分析。特别是，参与Wnt，Sonic Hedgehog和PIP 3信号通路的癌症相关基因的功能进行了深入分析。通过这些研究，我们已经成功地显示了大量的证据，在体内调节致癌过程的分子机制。此外，我们还成功地建立了几种理想的人类癌变模型：例如，我们可以清楚地表明，在发育中的小脑外胚层细胞中Patched-1的失活可能抑制其生长停滞，从而导致小脑髓母细胞瘤的形成。我们还发现Pten可能在小鼠的多种组织中，如T细胞、角质形成细胞、肝细胞和前列腺上皮细胞中实际上作为PiP 3通路的负调节剂起作用，并且Pten失活实际上在这些组织中诱导肿瘤。这些信息可能有助于阐明人类致癌的分子机制。

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.