Functional analysis of LATS protein kinases, products of novel tumor-suppressor genes

新型抑癌基因产物 LATS 蛋白激酶的功能分析

• 批准号: 12670130
• 负责人: FUJIMOTO Jiro
• 金额: $ 1.6万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670130/
• 关键词: cell cycle; protein kinase; tumor-supressor genes; 細胞周期

The LATS1 and LATS2 genes are mammalian homologs of the Drosophila LATS (large tumor suppressor) gene that encodes a serine/threonine kinase. Although LATS2 is expressed in various human cancer cell lines, we identified some kidney tumor cell lines that do not express LATS2. Both LATS1 and Bcl-2 are highly phosphorylated in LATS2-positive but not in LATS2-deficient, paclitaxel-treated cells.In addition, LATS2-deficient cells are less sensitive to paclitaxel-induced apoptosis. Ectopic expression of LATS2 in LATS2-deficient cells restores paclitaxel sensitivity , resulting in the phosphorylation of LATS1 and Bcl-2, and the induction of apoptosis. These observations indicate that LATS2 is involved in M-phase progression through the control of LATS1 and Bcl-2 phosphorylation, thereby regulating cellular entry into apoptosis and suggest that the status of LATS kinase genes in clinical tumors may define their sensitivity to paclitaxel-mediated chemotherapy.

LATS1和LATS2基因是编码丝氨酸/苏氨酸激酶的果蝇LATS（大肿瘤抑制剂）基因的哺乳动物同源物。尽管LATS2在各种人类癌细胞系中表达，但我们发现了一些不表达LATS2的肾脏肿瘤细胞系。 LATS1和Bcl-2在LATS2阳性中都高度磷酸化，但在LATS2缺陷的，紫杉醇处理的细胞中均未磷酸化。此外，LATS2缺陷型细胞对紫杉醇诱导的凋亡的敏感性较小。 LATS2在LATS2缺陷型细胞中的异位表达恢复了紫杉醇的敏感性，从而导致LATS1和BCL-2的磷酸化，并诱导凋亡。这些观察结果表明，LATS2通过控制LATS1和BCL-2磷酸化参与M期的进展，从而调节细胞进入细胞凋亡，并表明临床肿瘤中LATS激酶基因的状态可能定义其对Paclitaxel介导的化学疗法的敏感性。