Involvement of p38alpha 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 p38alpha) that is particularly strong during mitosis. In p53(-/-) tetraploid cells, phosphorylated p38alpha accumulated at centrosomes during the metaphase and at midbodies during the telophase. Selective knockdown or pharmacological inhibition of p38alpha 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 p38alpha, revealing a novel function for this protein in the context of aneuploidizing cell divisions.
Vitale
Ilio
I
INSERM, U848, Villejuif, France.
Jemaà
Mohamed
M
Senovilla
Laura
L
Galluzzi
Lorenzo
L
Rello-Varona
Santiago
S
Metivier
Didier
D
Ripoche
Hugues
H
Lazar
Vladimir
V
Dessen
Philippe
P
Castedo
Maria
M
Kroemer
Guido
G
D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D006801:Humans; D008677:Metaphase; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D010766:Phosphorylation; D011123:Polyploidy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013692:Telophase; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D048308:Mitogen-Activated Protein Kinase 14