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Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-8 activity.

Authors
  • Matthess, Yves
  • Raab, Monika
  • Sanhaji, Mourad
  • Lavrik, Inna N
  • Strebhardt, Klaus
Type
Published Article
Journal
Molecular and Cellular Biology
Publisher
American Society for Microbiology
Publication Date
Dec 01, 2010
Volume
30
Issue
24
Pages
5726–5740
Identifiers
DOI: 10.1128/MCB.00731-10
PMID: 20937773
Source
Medline
License
Unknown

Abstract

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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