title: DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis.
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.
authors: 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].
authors: Ataman
authors: A
authors: Sendoel
authors: German Center for Neurodegenerative Diseases (DZNE) e.V. Ludwig-Erhard-Allee 2, D-53175 Bonn, Germany.
authors: Simona
authors: S
authors: Maida
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
authors: Xue
authors: X
authors: Zheng
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
authors: Youjin
authors: Y
authors: Teo
authors: 1] Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland [2].
authors: Lilli
authors: L
authors: Stergiou
authors: German Center for Neurodegenerative Diseases (DZNE) e.V. Ludwig-Erhard-Allee 2, D-53175 Bonn, Germany.
authors: Carlo-Alberto
authors: CA
authors: Rossi
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
authors: Deni
authors: D
authors: Subasic
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
authors: Sergio M
authors: SM
authors: Pinto
authors: Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA.
authors: Jason M
authors: JM
authors: Kinchen
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
authors: Moyin
authors: M
authors: Shi
authors: Division of Hematology, University Hospital Zurich, Raemistrasse 190 CH-8091 Zurich, Switzerland.
authors: Steffen
authors: S
authors: Boettcher
authors: Nicholas School of the Environment, Duke University, Durham, North Carolina 27708, USA.
authors: Joel N
authors: JN
authors: Meyer
authors: Division of Hematology, University Hospital Zurich, Raemistrasse 190 CH-8091 Zurich, Switzerland.
authors: Markus G
authors: MG
authors: Manz
authors: German Center for Neurodegenerative Diseases (DZNE) e.V. Ludwig-Erhard-Allee 2, D-53175 Bonn, Germany.
authors: Daniele
authors: D
authors: Bano
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.
authors: Michael O
authors: MO
authors: Hengartner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D019143:Evolution, Molecular; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism*; D017238:Genes, Helminth / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D050257:Tubulin Modulators / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; C504038:Ced-13 protein, C elegans; C584411:DEPDC1 protein, human; C112486:EGL-1 protein, C elegans; D044385:GTP-Binding Protein alpha Subunits; D020690:GTPase-Activating Proteins; C467518:LET-99 protein, C elegans; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D050257:Tubulin Modulators; D014750:Vincristine