Sequential Cdk1 and Plk1 phosphorylation of caspase-8 triggers apoptotic cell death during mitosis.
Caspase-8 is crucial for cell death induction, especially via the death receptor pathway. The dysregulated expression or function of caspase-8 can promote tumor formation, progression and treatment resistance in different human cancers. Here, we show procaspase-8 is regulated during the cell cycle through the concerted inhibitory action of Cdk1/cyclin B1 and polo-like kinase 1 (Plk1). By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis. Thus, the clinical Plk1 inhibitor BI 2536 decreases the threshold of different cancer cell types toward Fas-induced cell death.
Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
Yves
Y
Matthess
Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Head and Neck Center, UKE Hamburg, Martinistr. 52, 20246 Hamburg, Germany.
Monika
M
Raab
Head and Neck Center, UKE Hamburg, Martinistr. 52, 20246 Hamburg, Germany.
Rainald
R
Knecht
Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Sven
S
Becker
Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: strebhardt@em.uni-frankfurt.de.
Klaus
K
Strebhardt
D017209:Apoptosis; D016203:CDC2 Protein Kinase; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D016203:CDC2 Protein Kinase; D053181:Caspase 8; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C528899:CDK1 protein, human
Apoptosis; Cell cycle; Polo-like kinase