Onset of quiescence following p53 mediated down-regulation of H2AX in normal cells.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Down-Regulation*; Fibroblasts/*metabolism ; Histones/*metabolism ; Tumor Suppressor Protein p53/*metabolism; Animals ; Blotting, Western ; Cell Line, Transformed ; Cell Proliferation/drug effects ; Cells, Cultured ; Cellular Senescence/drug effects ; Cytotoxins/pharmacology ; Diploidy ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Gene Expression/drug effects ; Genomic Instability ; Histones/genetics ; Mice ; Mice, Knockout ; Polyploidy ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Suppressor Protein p53/genetics ; Zinostatin/pharmacology
    • Abstract:
      Normal cells, both in vivo and in vitro, become quiescent after serial cell proliferation. During this process, cells can develop immortality with genomic instability, although the mechanisms by which this is regulated are unclear. Here, we show that a growth-arrested cellular status is produced by the down-regulation of histone H2AX in normal cells. Normal mouse embryonic fibroblast cells preserve an H2AX diminished quiescent status through p53 regulation and stable-diploidy maintenance. However, such quiescence is abrogated under continuous growth stimulation, inducing DNA replication stress. Because DNA replication stress-associated lesions are cryptogenic and capable of mediating chromosome-bridge formation and cytokinesis failure, this results in tetraploidization. Arf/p53 module-mutation is induced during tetraploidization with the resulting H2AX recovery and immortality acquisition. Thus, although cellular homeostasis is preserved under quiescence with stable diploidy, tetraploidization induced under growth stimulation disrupts the homeostasis and triggers immortality acquisition.
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    • Accession Number:
      0 (Cytotoxins)
      0 (H2AX protein, mouse)
      0 (Histones)
      0 (Tumor Suppressor Protein p53)
      9014-02-2 (Zinostatin)
    • Publication Date:
      Date Created: 20110823 Date Completed: 20120215 Latest Revision: 20211020
    • Publication Date:
      20221213
    • Accession Number:
      PMC3155552
    • Accession Number:
      10.1371/journal.pone.0023432
    • Accession Number:
      21858116