Involvement of p38α in the mitotic progression of p53^-/- tetraploid cells

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 p38α) that is particularly strong during mitosis. In p53^-/- tetraploid cells, phosphorylated p38α accumulated at centrosomes during the metaphase and at midbodies during the telophase. Selective knockdown or pharmacological inhibition of p38α 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 p38α, revealing a novel function for this protein in the context of aneuploidizing cell divisions.