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(大肿瘤抑制因子)基因在哺乳动物中的同源物。虽然LATS2在各种人类癌细胞中都有表达，但我们发现了一些不表达LATS2的肾肿瘤细胞株。在LATS2阳性的细胞中，LATS1和Bcl2都高度磷酸化，但在LATS2缺陷的紫杉醇处理的细胞中不是。此外，LATS2缺陷的细胞对紫杉醇诱导的细胞凋亡不那么敏感。在LATS2基因缺陷的细胞中异位表达LATS2可恢复紫杉醇的敏感性，导致LATS1和Bcl2的磷酸化，并诱导细胞凋亡。这些观察结果表明，LATS2通过控制LATS1和Bcl2的磷酸化而参与M期进展，从而调节细胞进入细胞凋亡，提示临床肿瘤中LATS激酶基因的状态可能决定了它们对紫杉醇介导的化疗的敏感性。