title: p53 dependent centrosome clustering prevents multipolar mitosis in tetraploid cells.
abstract: BACKGROUND
  p53 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.
  
  
  RESULTS
  Live 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%.
  
  
  CONCLUSIONS
  p53 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.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Yi
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhao
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.forename: Tieliang
authors.initials: T
authors.lastname: Ma
authors.forename: Yingyin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Heli
authors.initials: H
authors.lastname: Hou
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Cooke
authors.forename: Da-Qing
authors.initials: DQ
authors.lastname: Yang
authors.forename: Mian
authors.initials: M
authors.lastname: Wu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Shi
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D018385:Centrosome / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D042822:Genomic Instability; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology*; D008941:Spindle Apparatus / Q000502:physiology; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D020742:rhoA GTP-Binding Protein
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