Article ; Online: DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis.
2014 Volume 16, Issue 8, Page(s) 812–820
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Apoptosis/physiology ; Caenorhabditis elegans/cytology ; Caenorhabditis elegans/drug effects ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Evolution, Molecular ; GTP-Binding Protein alpha Subunits/metabolism ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Genes, Helminth/drug effects ; HeLa Cells ; Humans ; MAP Kinase Signaling System ; MCF-7 Cells ; Microtubules/genetics ; Microtubules/metabolism ; Mutation ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Phosphorylation/drug effects ; Proteolysis/drug effects ; RNA Interference ; Repressor Proteins/genetics ; Signal Transduction/genetics ; Tubulin Modulators/pharmacology ; Vincristine/pharmacology | ||||||||||
| Chemical Substances | Caenorhabditis elegans Proteins ; Ced-13 protein, C elegans ; DEPDC1 protein, human ; EGL-1 protein, C elegans ; GTP-Binding Protein alpha Subunits ; GTPase-Activating Proteins ; LET-99 protein, C elegans ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; Repressor Proteins ; Tubulin Modulators ; Vincristine (5J49Q6B70F) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2014-07-27 | ||||||||||
| Publishing country | England | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 1474722-4 | ||||||||||
| ISSN | 1476-4679 ; 1465-7392 | ||||||||||
| ISSN (online) | 1476-4679 | ||||||||||
| ISSN | 1465-7392 | ||||||||||
| DOI | 10.1038/ncb3010 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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