The role of p53 in the response to mitotic spindle damage

D W Meek

    Research output: Contribution to journalArticle

    53 Citations (Scopus)

    Abstract

    The p53 tumour suppressor protein has defined roles in G1/S and G2/M cell cycle checkpoints in response to a range of cellular stresses including DNA damage, dominant oncogene expression, hypoxia, metabolic changes and viral infection. In addition to these responses, p53 can also be activated when damage occurs to the mitotic spindle. Initially, spindle damage activates a p53-independent checkpoint which functions at the metaphase-anaphase transition and prevents cells from progressing through mitosis until the completion of spindle formation. Cells eventually escape from this block (a process termed 'mitotic slippage'), and an aberrant mitosis ensues in which sister chromatids fail to segregate properly. After a delay period, p53 responds to this mitotic failure by instituting a G1-like growth arrest, with an intact nucleus containing 4N DNA, but without the cells undergoing division. Cells lacking wild-type p53 are still able to arrest transiently at mitosis, and also fail to undergo division, underscoring that the delay in mitosis is p53-independent. However, these cells are not prevented from re-entering the cell cycle and can reduplicate their DNA unchecked, leading to polyploidy. Additionally, p53-null cells which experience spindle failure often show the appearance of micronuclei arising from poorly segregated chromosomes which have decondensed and been enclosed in a nuclear envelope. The ability of p53 to prevent their formation suggests an additional G2 involvement which prevents nuclear breakdown prior to mitosis. The molecular mechanism by which p53 is able to sense mitotic failure is still unknown, but may be linked to the ability of p53 to regulate duplication of the centrosome, the organelle which nucleates spindle formation.
    Original languageEnglish
    Pages (from-to)246-54
    Number of pages9
    JournalPathologie-Biologie
    Volume48
    Issue number3
    Publication statusPublished - Apr 2000

    Fingerprint

    Spindle Apparatus
    Mitosis
    G2 Phase Cell Cycle Checkpoints
    Tumor Suppressor Protein p53
    Null Lymphocytes
    Centrosome
    Anaphase
    Chromatids
    Polyploidy
    DNA
    Nuclear Envelope
    Virus Diseases
    Metaphase
    Oncogenes
    Organelles
    Cell Division
    DNA Damage
    Cell Cycle
    Chromosomes
    Growth

    Cite this

    Meek, D W. / The role of p53 in the response to mitotic spindle damage. In: Pathologie-Biologie. 2000 ; Vol. 48, No. 3. pp. 246-54.
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    The role of p53 in the response to mitotic spindle damage. / Meek, D W.

    In: Pathologie-Biologie, Vol. 48, No. 3, 04.2000, p. 246-54.

    Research output: Contribution to journalArticle

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