Abstract
Backgroundp53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy.Principal FindingsLive cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%.Conclusionsp53 could not prevent tetraploid cells entering mitosis or induce tetraploid cell death. However, p53 abnormality impaired centrosome clustering and lead to multipolar mitosis in tetraploid cells by modulating the RhoA/ROCK signaling pathway.
Highlights
Aneuploidy, the condition in which a cell has extra or missing chromosomes, is the most common characteristic of human cancers and is linked to the progressive development of highgrade, invasive tumors
Over-activated RhoA contributes to multipolar mitosis in p53 deficient tetraploid cells We studied the mechanism by which p53 deficiency impairs the clustering of extra centrosomes and promotes multipolar mitosis in tetraploid cells
Given that inactivation of p53 in tetraploid cells results in progression toward aneuploidy and tumorigenesis [9], a p53 dependent ‘‘tetraploidy checkpoint’’ which could prevent the tetraploid cells from entering mitosis has been proposed [4,49]
Summary
Aneuploidy, the condition in which a cell has extra or missing chromosomes, is the most common characteristic of human cancers and is linked to the progressive development of highgrade, invasive tumors. Despite this crucial role, its origins remain elusive. A long-standing hypothesis is that a genetically metastable tetraploid intermediate could facilitate the development of aneuploid malignancies [1,2,3] This assumption is supported by researches in both cultured cells [4] and animal models [5]. Further support comes from the observation that p53-/- tetraploid mouse mammary epithelial cells (MMECs) induced malignant mammary epithelial cancers after subcutaneous injection into nude mice, while p53-/- diploid and p53+/+ tetraploid MMECs did not [9]
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