JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

Abstract

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.

Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

“…miR-26a decreases expression of the tumor suppressors PTEN and RB1 and inhibits expression of MAP3K2/MEKK2, an activator of c-Jun N-terminal kinase (JNK) (12). JNK has also been implicated in tumor suppression (13). In this manner, miR-26a transforms NIH 3T3 cells and cooperates with CDK4 and CENTG1 to increase GBM growth.…”

“…We also identified MAP3K2/MEKK2, an activator of the JNK pathway, which has been implicated in apoptosis and tumor suppression (13,19). Thus, PTEN, RB1, and MAP3K2/MEKK2 were chosen for further study.…”

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

“…Mutant larvae can survive up to early pupal stages and exhibit overgrowth of the central nervous system (CNS) at the white prepupal stage (Fig. 1 C-E), as described previously (65). To analyze the brain overgrowth phenotype in more detail, we quantified the volume of the VNC and OL compartments separately.…”

Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

“…29 Additionally, some studies found that JNK is another potent downstream kinase, which accounts for LKB1- induced apoptosis. 30 JNK can initiate cytochrome c release to mediate mitochondrial apoptosis signaling pathway, which is an essential procedure of cisplatin-mediated cell apoptosis. 31 These studies assume that LKB1-enhancing cisplatin-mediated NSCLC cell apoptosis may be partly through p53-and JNK-related signaling pathways.…”