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Nat Cell Biol. 2014 Aug;16(8):812-20. doi: 10.1038/ncb3010. Epub 2014 Jul 27.

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

Author information

1
1] Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland [2] Division of Hematology, University Hospital Zurich, Raemistrasse 190 CH-8091 Zurich, Switzerland [3].
2
German Center for Neurodegenerative Diseases (DZNE) e.V. Ludwig-Erhard-Allee 2, D-53175 Bonn, Germany.
3
Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
4
1] Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland [2].
5
Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA.
6
Division of Hematology, University Hospital Zurich, Raemistrasse 190 CH-8091 Zurich, Switzerland.
7
Nicholas School of the Environment, Duke University, Durham, North Carolina 27708, USA.

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.

Comment in

PMID:
25064737
DOI:
10.1038/ncb3010
[Indexed for MEDLINE]

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