JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila
JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila
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DOI：
10.1038/sj.cdd.4401790
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发表时间：
2006-07-01
影响因子：
12.4
通讯作者：
Chung, J.
中科院分区：
文献类型：
--
作者：
Lee, J. H.;Koh, H.;Chung, J.
虽然最近的进展已经揭示了LKB 1在体内的多种功能，但控制这些过程的详细分子机制仍然是谜。在这里，我们发现，果蝇LKB 1负调控器官生长的半胱天冬酶依赖性细胞凋亡，而不影响细胞大小和细胞周期进程。通过对LKB 1修饰剂的基因筛选，我们发现JNK通路是LKB 1信号通路的一个新的组成部分，它被LKB 1激活并介导LKB 1依赖的细胞凋亡。一致的是，LKB 1-null突变体是有缺陷的胚胎细胞凋亡，并显示在中枢神经系统的急剧增生，这些表型完全救出异位JNK激活以及野生型LKB 1的表达。此外，抑制LKB 1导致上皮形态发生失败，这与JNK活性降低有关。总的来说，我们的研究前所未有地阐明了JNK作为LKB 1依赖性细胞凋亡的下游介质，并为了解LKB 1在体内的多种功能提供了新的范式。
Although recent progresses have unveiled the diverse in vivo functions of LKB1, detailed molecular mechanisms governing these processes still remain enigmatic. Here, we showed that Drosophila LKB1 negatively regulates organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, we discovered the JNK pathway as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Consistently, LKB1-null mutant was defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression. Furthermore, inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. Collectively, our studies unprecedentedly elucidate JNK as the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo.