Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Department of Obstetrics and Gynecology, School of Medicine, J W Goethe University, Frankfurt, Germany.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2010; 30(24):5726-40. DOI: 10.1128/MCB.00731-10
Source: PubMed


Caspase activation is a hallmark of apoptosis. However, the molecular mechanisms underlying the regulation of caspase-8 activation
within the extrinsic death pathway are not well understood. In this study, we demonstrate that procaspase-8 is phosphorylated
in mitotic cells by Cdk1/cyclin B1 on Ser-387, which is located at the N terminus of the catalytic subunit p10. This phosphorylation
of procaspase-8 on Ser-387 occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. Furthermore,
RNA interference-mediated silencing of cyclin B1 or treatment with the Cdk1 inhibitor RO-3306 enhances the Fas-mediated activation
and processing of procaspase-8 in mitotic cells. A nonphosphorylatable procaspase-8 (S387A) facilitates Fas-induced apoptosis
during mitosis. Our findings suggest that Cdk1/cyclin B1 activity shields human cells against extrinsic death stimuli and
unravel the molecular details of the cross talk between cell cycle and extrinsic apoptotic pathways. Finally, this new mechanism
may also contribute to tumorigenesis.

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Available from: Klaus Strebhardt
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    • "This report presents a novel regulatory mechanism involving the action of Cdk1/cyclin B1 and Plk1 upon their common substrate procaspase-8. Previously, we could demonstrate that procaspase-8 is phosphorylated in mitotic cells by Cdk1/ cyclin B1 on S387, which is located at the N terminus of the catalytic subunit p10 (Matthess et al., 2010). Inhibition of Cdk1 activity by depletion of cyclin B1 or the use of the Cdk1 inhibitor RO-3306 enhanced the Fas-mediated activation and processing of procaspase-8 in mitotic cells suggesting the possibility that Cdk1/cyclin B1 alone exerts the anti-apoptotic effect in mitotic cells. "
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    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.
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    • "Overexpression of cyclin B1, the regulatory subunit for Cdk1, is overexpressed in non-small cell lung cancer and its upregulation is closely associated with poor prognosis [120]. Currently, inhibition of cyclin-dependent kinases, such as Cdk1, is being considered as a therapeutic target to increase the sensitivity of cancer cells to extrinsic cell death [121] and prohibit metastatic processes [122]. "
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    • "Over the years, different groups have been able to identify a handful of kinases that can carry out such phosphorylation. The p38 MAPK can phosphorylate pro-Caspase-8 at Ser364 (Alvarado-Kristensson et al., 2004), the Src kinase at Tyr380 (Cursi et al., 2006), CDK1 at Ser387 (Matthess et al., 2010) and finally RSK2 at Thr263 (Peng et al., 2011). Active ERK 1/2 have also been reported to protect cancer cells from undergoing apoptosis in the presence of cytotoxic agents like Trail, FasL or TNFa and we intended to determine the mechanism(s) behind this anti-apoptotic function of pERK 1/2 (Holmstrom et al., 1998, 2000; Lee et al., 2005; Liu et al., 2004; Pucci et al., 2009; Tran et al., 2001; Zhang et al., 2003). "
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    ABSTRACT: ERK 1/2 are found to be hyperactive in many cancers. Active ERK 1/2 (pERK 1/2) are known to protect cancer cells from undergoing death receptor-mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through in vitro kinase assays and mass-spectrometry we demonstrate that pERK 1/2 can phosphorylate pro-Caspase-8 at S387. Also, in EGFR-overexpressing Type I and II ovarian and breast cancer cell lines respectively, ERK 1/2 remain active only during the interphase. During this period, pERK 1/2 could inhibit Trail-induced apoptosis, most effectively during the G1/S phase. By knocking-down the endogenous pro-Caspase-8 using RNAi and replacing it with its non-phosphorylatable counterpart (S387A), a significant increase in Caspase-8 activity upon Trail stimulation was observed, even in the presence of pERK 1/2. Taken together, we propose that a combination of Trail and an inhibitor of ERK 1/2 activities could potentially enhance of Trail’s effectiveness as an anti-cancer agent in ERK 1/2 hyperactive cancer cells.
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