Journal
CELL CYCLE
Volume 9, Issue 14, Pages 2823-2829Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.9.14.12254
Keywords
aneuploidy; apoptosis; centrosome; colon carcinoma; MOS
Categories
Funding
- Ligue Nationale contre le Cancer
- Agence Nationale pour la Recherche (ANR)
- European Commission
- Fondation pour la Recherche Medicale (FRM)
- Institut National du Cancer (INCa)
- Canceropole Ile-deFrance
- Association pour la Recherche sur le Cancer (ARC)
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The tumor suppressor protein p53 plays a major role in preserving genomic stability. p53 suppresses a pathway leading from normal diploidy to neoplastic aneuploidy (via an intermediate metastable stage of tetraploidy) at two levels: first by preventing the generation/survival of tetraploid cells, and second by repressing their aberrant multipolar division. Here, we report the characterization of p53(-/-) tetraploid cells, which-at difference with both their p53(-/-) diploid and their p53(+/+) tetraploid counterparts-manifest a marked hyperphosporylation of the mitogen-activated protein kinase MAPK14 (best known as p38 alpha) that is particularly strong during mitosis. In p53(-/-) tetraploid cells, phosphorylated p38 alpha accumulated at centrosomes during the metaphase and at midbodies during the telophase. Selective knockdown or pharmacological inhibition of p38 alpha had a dramatic effect on p53(-/-) (but not p53(+/+)) tetraploids, causing the activation of the spindle assembly checkpoint, an arrest during the metaphase, a major increase in abnormal bipolar and monopolar mitoses, as well as an increment in the generation of multinuclear cells. We conclude that the mitotic progression of p53(-/-) (but not p53(+/+)) tetraploids heavily relies on p38a, revealing a novel function for this protein in the context of aneuploidizing cell divisions.
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