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Mol Oncol. 2014 May;8(3):596-608. doi: 10.1016/j.molonc.2013.12.013. Epub 2014 Jan 17.

Sequential Cdk1 and Plk1 phosphorylation of caspase-8 triggers apoptotic cell death during mitosis.

Author information

1
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.
2
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.
3
Head and Neck Center, UKE Hamburg, Martinistr. 52, 20246 Hamburg, Germany.
4
Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
5
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.

Abstract

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.

KEYWORDS:

Apoptosis; Cell cycle; Polo-like kinase

PMID:
24484936
PMCID:
PMC5528627
DOI:
10.1016/j.molonc.2013.12.013
[Indexed for MEDLINE]
Free PMC Article

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