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，包括小鼠条件基因靶向技术，对许多癌症相关基因，如肿瘤抑制基因和致癌基因进行了功能分析。特别是对参与Wnt、Sonic Hedgehog和PIP3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，我们已经成功地展示了调控体内癌变过程的分子机制的大量证据。此外，我们还成功地建立了几个理想的人类癌变模型：例如，我们可以清楚地表明，发育中的小脑外生发层细胞中patch -1的失活可能会抑制其生长停滞，从而导致小脑成神经管细胞瘤的形成。我们也可以证明Pten实际上可能在小鼠的多种组织中，如T细胞、角化细胞、肝细胞和前列腺上皮细胞中，作为PiP3通路的负调节因子，Pten失活实际上诱发了这些组织中的肿瘤。这些信息可能对阐明人类癌变的分子机制有很大的帮助。

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.