Reference : Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint t...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28.
Muller, Ines [> >]
Strozyk, Elwira [> >]
Schindler, Sebastian [> >]
Beissert, Stefan [> >]
Oo, Htoo Zarni [> >]
Sauter, Thomas mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Lucarelli, Philippe [> >]
Raeth, Sebastian [> >]
Hausser, Angelika [> >]
Al Nakouzi, Nader [> >]
Fazli, Ladan [> >]
Gleave, Martin E. [> >]
Liu, He [> >]
Simon, Hans-Uwe [> >]
Walczak, Henning [> >]
Green, Douglas R. [> >]
Bartek, Jiri [> >]
Daugaard, Mads [> >]
Kulms, Dagmar [> >]
Molecular cell
Yes (verified by ORBilu)
United States
[en] G2/M checkpoint ; USP28 ; apoptosis ; cancer ; caspase-8 ; p53
[en] Cytosolic caspase-8 is a mediator of death receptor signaling. While caspase-8 expression is lost in some tumors, it is increased in others, indicating a conditional pro-survival function of caspase-8 in cancer. Here, we show that tumor cells employ DNA-damage-induced nuclear caspase-8 to override the p53-dependent G2/M cell-cycle checkpoint. Caspase-8 is upregulated and localized to the nucleus in multiple human cancers, correlating with treatment resistance and poor clinical outcome. Depletion of caspase-8 causes G2/M arrest, stabilization of p53, and induction of p53-dependent intrinsic apoptosis in tumor cells. In the nucleus, caspase-8 cleaves and inactivates the ubiquitin-specific peptidase 28 (USP28), preventing USP28 from de-ubiquitinating and stabilizing wild-type p53. This results in de facto p53 protein loss, switching cell fate from apoptosis toward mitosis. In summary, our work identifies a non-canonical role of caspase-8 exploited by cancer cells to override the p53-dependent G2/M cell-cycle checkpoint.
Copyright (c) 2020 Elsevier Inc. All rights reserved.
H2020 ; 642295 - MEL-PLEX - Exploiting MELanoma disease comPLEXity to address European research training needs in translational cancer systems biology and cancer systems medicine
FnR ; FNR7643621 > Thomas Sauter > Melanoma sensitivity > Predicting individual sensitivity of malignant melanoma to combination therapies by statistical and network modeling on innovative 3D organotypic screening models > 01/05/2015 > 30/04/2018 > 2013

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