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Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis

(2014) CELL DEATH AND DIFFERENTIATION. 21(3). p.416-426
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Abstract
Cytotoxic lymphocyte protease granzyme M (GrM) is a potent inducer of tumor cell death. The apoptotic phenotype and mechanism by which it induces cell death, however, remain poorly understood and controversial. Here, we show that GrM-induced cell death was largely caspase-dependent with various hallmarks of classical apoptosis, coinciding with caspase-independent G2/M cell cycle arrest. Using positional proteomics in human tumor cells, we identified the nuclear enzyme topoisomerase II alpha (topoll alpha) as a physiological substrate of GrM. Cleavage of topoll alpha by GrM at Leu(1280) separated topoll alpha functional domains from the nuclear localization signals, leading to nuclear exit of topoll alpha catalytic activity, thereby rendering it nonfunctional. Similar to the apoptotic phenotype of GrM, topoll alpha depletion in tumor cells led to cell cycle arrest in G2/M, mitochondrial perturbations, caspase activation, and apoptosis. We conclude that cytotoxic lymphocyte protease GrM targets topoll alpha to trigger cell cycle arrest and caspase-dependent apoptosis.
Keywords
CLEAVAGE, INHIBITOR, EXPRESSION, PERFORIN, HNRNP K, TUMOR-CELLS, ORPHAN GRANZYMES, MEDIATED APOPTOSIS, B-INDUCED APOPTOSIS, SERINE-PROTEASE GRANZYME, apoptosis, protease, topoisomerase II alpha, cell cycle arrest, granzyme M

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Chicago
de Poot, SAH, KW Lai, L van der Wal, Kim Plasman, Petra Van Damme, AC Porter, Kris Gevaert, and N Bovenschen. 2014. “Granzyme M Targets Topoisomerase II Alpha to Trigger Cell Cycle Arrest and Caspase-dependent Apoptosis.” Cell Death and Differentiation 21 (3): 416–426.
APA
de Poot, S., Lai, K., van der Wal, L., Plasman, K., Van Damme, P., Porter, A., Gevaert, K., et al. (2014). Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis. CELL DEATH AND DIFFERENTIATION, 21(3), 416–426.
Vancouver
1.
de Poot S, Lai K, van der Wal L, Plasman K, Van Damme P, Porter A, et al. Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis. CELL DEATH AND DIFFERENTIATION. 2014;21(3):416–26.
MLA
de Poot, SAH, KW Lai, L van der Wal, et al. “Granzyme M Targets Topoisomerase II Alpha to Trigger Cell Cycle Arrest and Caspase-dependent Apoptosis.” CELL DEATH AND DIFFERENTIATION 21.3 (2014): 416–426. Print.
@article{4352552,
  abstract     = {Cytotoxic lymphocyte protease granzyme M (GrM) is a potent inducer of tumor cell death. The apoptotic phenotype and mechanism by which it induces cell death, however, remain poorly understood and controversial. Here, we show that GrM-induced cell death was largely caspase-dependent with various hallmarks of classical apoptosis, coinciding with caspase-independent G2/M cell cycle arrest. Using positional proteomics in human tumor cells, we identified the nuclear enzyme topoisomerase II alpha (topoll alpha) as a physiological substrate of GrM. Cleavage of topoll alpha by GrM at Leu(1280) separated topoll alpha functional domains from the nuclear localization signals, leading to nuclear exit of topoll alpha catalytic activity, thereby rendering it nonfunctional. Similar to the apoptotic phenotype of GrM, topoll alpha depletion in tumor cells led to cell cycle arrest in G2/M, mitochondrial perturbations, caspase activation, and apoptosis. We conclude that cytotoxic lymphocyte protease GrM targets topoll alpha to trigger cell cycle arrest and caspase-dependent apoptosis.},
  author       = {de Poot, SAH and Lai, KW and van der Wal, L and Plasman, Kim and Van Damme, Petra and Porter, AC and Gevaert, Kris and Bovenschen, N},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keywords     = {CLEAVAGE,INHIBITOR,EXPRESSION,PERFORIN,HNRNP K,TUMOR-CELLS,ORPHAN GRANZYMES,MEDIATED APOPTOSIS,B-INDUCED APOPTOSIS,SERINE-PROTEASE GRANZYME,apoptosis,protease,topoisomerase II alpha,cell cycle arrest,granzyme M},
  language     = {eng},
  number       = {3},
  pages        = {416--426},
  title        = {Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis},
  url          = {http://dx.doi.org/10.1038/cdd.2013.155},
  volume       = {21},
  year         = {2014},
}

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