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On the road to cancer: aneuploidy and the mitotic checkpoint

On the road to cancer: aneuploidy and the mitotic checkpoint Aneuploidy, or abnormal chromosome content, is the most common characteristic of human solid tumours. Aneuploidy might contribute to tumour formation and is associated with acquired resistance to some chemotherapeutics. Tumour cells become aneuploid as a result of aberrant mitotic divisions. These aberrant divisions are caused by divisions with a multipolar spindle as a result of previous defects in cytokinesis or centrosome amplification, by defects in chromosome cohesion, by spindle attachment defects, or by impairment of the mitotic checkpoint response. The mitotic checkpoint is a signalling cascade that arrests the cell cycle in mitosis when even a single chromosome is not properly attached to the mitotic spindle. This arrest is achieved by inhibiting the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that is essential for mitotic progression. Many tumour cells have a diminished, but not absent, mitotic checkpoint response. Mouse models in which mitotic checkpoint signalling is decreased show an increase in spontaneous or carcinogen-induced tumour formation. Mutations in mitotic checkpoint genes themselves are not a common mechanism of checkpoint impairment in human tumour cells. Mitotic checkpoint impairment and aneuploidy in human tumour cells are often associated with changes in the protein levels of mitotic checkpoint proteins. In some tumour cells, these changes occur through altered transcriptional regulation by tumour suppressors or oncogene products. Complete inactivation of mitotic checkpoint signalling causes cell-autonomous lethality. Drugs that specifically and efficiently interfere with mitotic checkpoint signalling could therefore be useful as anticancer agents. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Cancer Springer Journals

On the road to cancer: aneuploidy and the mitotic checkpoint

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References (227)

Publisher
Springer Journals
Copyright
Copyright © 2005 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Cancer Research
ISSN
1474-175X
eISSN
1474-1768
DOI
10.1038/nrc1714
Publisher site
See Article on Publisher Site

Abstract

Aneuploidy, or abnormal chromosome content, is the most common characteristic of human solid tumours. Aneuploidy might contribute to tumour formation and is associated with acquired resistance to some chemotherapeutics. Tumour cells become aneuploid as a result of aberrant mitotic divisions. These aberrant divisions are caused by divisions with a multipolar spindle as a result of previous defects in cytokinesis or centrosome amplification, by defects in chromosome cohesion, by spindle attachment defects, or by impairment of the mitotic checkpoint response. The mitotic checkpoint is a signalling cascade that arrests the cell cycle in mitosis when even a single chromosome is not properly attached to the mitotic spindle. This arrest is achieved by inhibiting the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that is essential for mitotic progression. Many tumour cells have a diminished, but not absent, mitotic checkpoint response. Mouse models in which mitotic checkpoint signalling is decreased show an increase in spontaneous or carcinogen-induced tumour formation. Mutations in mitotic checkpoint genes themselves are not a common mechanism of checkpoint impairment in human tumour cells. Mitotic checkpoint impairment and aneuploidy in human tumour cells are often associated with changes in the protein levels of mitotic checkpoint proteins. In some tumour cells, these changes occur through altered transcriptional regulation by tumour suppressors or oncogene products. Complete inactivation of mitotic checkpoint signalling causes cell-autonomous lethality. Drugs that specifically and efficiently interfere with mitotic checkpoint signalling could therefore be useful as anticancer agents.

Journal

Nature Reviews Cancer – Springer Journals

Published: Oct 1, 2005

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