INSERM, U848, Villejuif, France.
Cell Cycle. 2010 Jul 15;9(14):2823-9. Epub 2010 Jul 3.
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.
肿瘤抑制蛋白 p53 在维持基因组稳定性方面发挥着重要作用。p53 在两个层面上抑制了从正常二倍体到肿瘤性非整倍体（通过四倍体的中间亚稳阶段）的途径：首先通过防止四倍体细胞的产生/存活，其次通过抑制它们异常的多极分裂。在这里，我们报告了 p53(-/-)四倍体细胞的特征，这些细胞与它们的 p53(-/-)二倍体和 p53(+/+)四倍体对应物不同，表现出明显的丝裂原激活蛋白激酶 MAPK14（最著名的是 p38alpha）的过度磷酸化，在有丝分裂期间尤为强烈。在 p53(-/-)四倍体细胞中，磷酸化的 p38alpha 在中期聚集在中心体上，在末期聚集在中间体上。p38alpha 的选择性敲低或药理学抑制对 p53(-/-)（但不是 p53(+/+)）四倍体有显著影响，导致纺锤体组装检查点的激活、中期停滞、异常双极和单极有丝分裂的大量增加，以及多核细胞的产生增加。我们得出结论，p53(-/-)（但不是 p53(+/+)）四倍体的有丝分裂进程严重依赖于 p38alpha，揭示了该蛋白在非整倍体细胞分裂中的新功能。
