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Nat Cell Biol. 2014 Aug;16(8):779-91. doi: 10.1038/ncb2994. Epub 2014 Jun 29.

Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells.

Author information

1
1] Institute of Molecular Oncology, Section for Cellular Oncology, Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Georg-August University, D-37077 Goettingen, Germany [2].
2
Institute for Pathology, University Medical Center, Ruprecht-Karls-University, D-69120 Heidelberg, Germany.
3
1] Institute for Pathology, University Medical Center, Ruprecht-Karls-University, D-69120 Heidelberg, Germany [2] German Consortium for Translational Cancer Research, D-69120 Heidelberg, Germany.
4
Institute for Human Genetics, University Medical Center, Georg-August University, D-37073 Goettingen, Germany.
5
Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, D-04107 Leipzig, Germany.
6
Department of Physiology and Biophysics, University of Washington, School of Medicine, Seattle, Washington 98195, USA.
7
Institute of Molecular Oncology, Section for Cellular Oncology, Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Georg-August University, D-37077 Goettingen, Germany.

Abstract

Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth.

PMID:
24976383
PMCID:
PMC4389786
DOI:
10.1038/ncb2994
[Indexed for MEDLINE]
Free PMC Article

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