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Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest

Mikule, Keith ; Delaval, Benedicte ; Kaldis, Philipp LU ; Jurcyzk, Agata ; Hergert, Polla and Doxsey, Stephen (2007) In Nature Cell Biology 9(2). p.160-170
Abstract

Centrosomes organize the microtubule cytoskeleton for both interphase and mitotic functions. They are implicated in cell-cycle progression but the mechanism is unknown. Here, we show that depletion of 14 out of 15 centrosome proteins arrests human diploid cells in G1 with reduced Cdk2-cyclin A activity and that expression of a centrosome-disrupting dominant-negative construct gives similar results. Cell-cycle arrest is always accompanied by defects in centrosome structure and function (for example, duplication and primary cilia assembly). The arrest occurs from within G1, excluding contributions from mitosis and cytokinesis. The arrest requires p38, p53 and p21, and is preceded by p38-dependent activation and centrosomal recruitment of... (More)

Centrosomes organize the microtubule cytoskeleton for both interphase and mitotic functions. They are implicated in cell-cycle progression but the mechanism is unknown. Here, we show that depletion of 14 out of 15 centrosome proteins arrests human diploid cells in G1 with reduced Cdk2-cyclin A activity and that expression of a centrosome-disrupting dominant-negative construct gives similar results. Cell-cycle arrest is always accompanied by defects in centrosome structure and function (for example, duplication and primary cilia assembly). The arrest occurs from within G1, excluding contributions from mitosis and cytokinesis. The arrest requires p38, p53 and p21, and is preceded by p38-dependent activation and centrosomal recruitment of p53. p53-deficient cells fail to arrest, leading to centrosome and spindle dysfunction and aneuploidy. We propose that loss of centrosome integrity activates a checkpoint that inhibits G1-S progression. This model satisfies the definition of a checkpoint in having three elements: a perturbation that is sensed, a transducer (p53) and a receiver (p21).

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author
publishing date
type
Contribution to journal
publication status
published
in
Nature Cell Biology
volume
9
issue
2
pages
160 - 170
publisher
Nature Publishing Group
external identifiers
  • pmid:17330329
  • scopus:33947270830
ISSN
1465-7392
DOI
10.1038/ncb1529
language
English
LU publication?
no
id
3009a80d-4447-4bac-bfa1-bd1057381506
date added to LUP
2019-09-18 14:17:19
date last changed
2020-05-26 05:32:24
@article{3009a80d-4447-4bac-bfa1-bd1057381506,
  abstract     = {<p>Centrosomes organize the microtubule cytoskeleton for both interphase and mitotic functions. They are implicated in cell-cycle progression but the mechanism is unknown. Here, we show that depletion of 14 out of 15 centrosome proteins arrests human diploid cells in G1 with reduced Cdk2-cyclin A activity and that expression of a centrosome-disrupting dominant-negative construct gives similar results. Cell-cycle arrest is always accompanied by defects in centrosome structure and function (for example, duplication and primary cilia assembly). The arrest occurs from within G1, excluding contributions from mitosis and cytokinesis. The arrest requires p38, p53 and p21, and is preceded by p38-dependent activation and centrosomal recruitment of p53. p53-deficient cells fail to arrest, leading to centrosome and spindle dysfunction and aneuploidy. We propose that loss of centrosome integrity activates a checkpoint that inhibits G1-S progression. This model satisfies the definition of a checkpoint in having three elements: a perturbation that is sensed, a transducer (p53) and a receiver (p21).</p>},
  author       = {Mikule, Keith and Delaval, Benedicte and Kaldis, Philipp and Jurcyzk, Agata and Hergert, Polla and Doxsey, Stephen},
  issn         = {1465-7392},
  language     = {eng},
  month        = {02},
  number       = {2},
  pages        = {160--170},
  publisher    = {Nature Publishing Group},
  series       = {Nature Cell Biology},
  title        = {Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest},
  url          = {http://dx.doi.org/10.1038/ncb1529},
  doi          = {10.1038/ncb1529},
  volume       = {9},
  year         = {2007},
}