DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apop

Abstract

Hengartner and colleagues use an RNAi-based screening approach in C. elegans to identify effectors of the chemotherapy drug vincristine. They report that the drug induces apoptosis by targeting a conserved LET-99–GPA-11–JNK1 pathway. Microtubule-targeting chemotherapeutics induce apoptosis in cancer cells by promoting the phosphorylation and degradation of the anti-apoptotic BCL-2 family member MCL1. The signalling cascade linking microtubule disruption to MCL1 degradation remains however to be defined. Here, we establish an in vivo screening strategy in Caenorhabditis elegans to uncover genes involved in chemotherapy-induced apoptosis. Using an RNAi-based screen, we identify three genes required for vincristine-induced apoptosis. We show that the DEP domain protein LET-99 acts upstream of the heterotrimeric G protein alpha subunit GPA-11 to control activation of the stress kinase JNK-1. The human homologue of LET-99, DEPDC1, similarly regulates vincristine-induced cell death by promoting JNK-dependent degradation of the BCL-2 family protein MCL1. Collectively, these data uncover an evolutionarily conserved mediator of anti-tubulin drug-induced apoptosis and suggest that DEPDC1 levels could be an additional determinant for therapy response upstream of MCL1.

Cite this article

Sendoel, A., Maida, S., Zheng, X. et al. DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis. Nat Cell Biol 16, 812–820 (2014). https://doi.org/10.1038/ncb3010

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