Fuctinonal analysis of cancer related genes by targeted mutagenesis in mice

通过小鼠靶向诱变进行癌症相关基因的功能分析

• 批准号: 12213009
• 负责人: NODA Tetsuo
• 金额: $ 145.73万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213009/
• 关键词: Patched; β-catenin; APC; PTEN; ジーンターゲティング; 癌抑制遺伝子; SMAD4遺伝子; VHL遺伝子; ARF遺伝子; PTEN遺伝子; ノックアウトマウス; p53遺伝子

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.

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。

项目成果

Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.

• DOI: 10.3892/ijo.24.4.977
• 发表时间: 2004-04
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Y. Hirai;Y. Kawamata;N. Takeshima;R. Furuta;T. Kitagawa;T. Kawaguchi;K. Hasumi;S. Sugai;T. Noda

Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.

• DOI: 10.1172/jci20513
• 发表时间: 2004-06
• 期刊: The Journal of clinical investigation
• 作者: Y. Horie;A. Suzuki;E. Kataoka;Takehiko Sasaki;K. Hamada;J. Sasaki;K. Mizuno;G. Hasegawa

Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells.

• DOI: 10.1083/jcb.200410083
• 发表时间: 2005-04-11
• 期刊: The Journal of cell biology
• 作者: Tamura A;Kikuchi S;Hata M;Katsuno T;Matsui T;Hayashi H;Suzuki Y;Noda T;Tsukita S;Tsukita S
• 通讯作者: Tsukita S

T.Noda, (他4名): "Distinct macroscopic structures developed from solutions of chemical compounds and periodic proteins."EMBO Rep.. 4(2). 148-153 (2003)

T.Noda，（其他 4 人）：“从化合物和周期性蛋白质的溶液中开发出独特的宏观结构。”EMBO Rep.. 148-153 (2003)。

T.Noda, (他5名): "Characterization of Folding Pathways of the Type-1 and Type-2 Periplasmic Binding Proteins MglB and ArgT."J.Biochem.. 133(3). 371-376 (2003)

T.Noda，（其他 5 名）：“1 型和 2 型周质结合蛋白 MglB 和 ArgT 折叠途径的表征”。J.Biochem.. 133(3) (2003)。