Centrosome Amplification and the Origin of Chromosomal Instability in Breast Cancer

Salisbury, Jeffrey L.

doi:10.1007/0-387-23761-5_9

Cited by 23 publications

(55 citation statements)

References 82 publications

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“…Consistent with this idea are the observations that inhibition of CDC25B results in the failure of the centrosome to assemble both daughter centrioles 3 and microtubules, whereas overexpression of CDC25B, on the other hand, results in overduplication of centrosomes and increased microtubule nucleation.…”

Section: Cdc25b and Centrosome Duplicationmentioning

confidence: 64%

“…Because inhibition or overexpression of CDC25B had inverse effects on both the duplication of centrosomes and microtubule nucleation (Figs. 1-4), 3 which have both been reported to be regulated by centrosomal accumulation of g-tubulin (28, 32-37), …”

Section: Cdc25b Overexpression Drives Centrosome Overduplicationmentioning

confidence: 99%

“…Centrosome amplification may result either from uncontrolled centrosome duplication or from cytokinetic failure (3,4). The centrosome functions essentially to maintain cell polarity during interphase and ensure bipolar spindle assembly in mitosis (5,6), and the components required for these activities are primarily comprised of g-tubulin, which, in association with additional proteins, forms g-tubulin ring complexes (gTuRC) that act as templates for microtubule nucleation (5,7).…”

Section: Introductionmentioning

confidence: 99%

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CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation

2007

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Centrosome amplification is frequently reported in human cancers, although the molecular mechanisms that are responsible for this remain unclear. There is significant evidence to support a role for cyclin-dependent kinase (CDK)-cyclin complexes in centrosome duplication. The activities of CDKcyclin complexes are, in turn, regulated by the CDC25 family of phosphatases in a strict spatiotemporal manner, and we have recently reported that CDC25B localizes to the centrosomes from early S phase. In the present study, we have investigated the role of centrosomally localized CDC25B in centrosome duplication. We first observed that overexpression of CDC25B under an inducible promoter in S phase results in centrosome overduplication. We found that forced expression of wild-type but not phosphatase-inactive CDC25B at the centrosomes results in centrosome amplification, aberrant microtubule organization, and abnormal accumulation of ;-tubulin. In contrast, inhibition of CDC25B phosphatase activity inhibits the assembly of interphase microtubules and the centrosomal localization of ;-tubulin. We propose that CDC25B is part of the pathway that controls the localization of ;-tubulin to the centrosomes, thereby regulating centrosome duplication during S phase and the nucleation of microtubules. We speculate that abnormal expression of CDC25B in numerous human tumors might therefore have a critical role in centrosome amplification and genomic instability. [Cancer Res 2007;67(24):11557-64]

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Section: Cdc25b and Centrosome Duplicationmentioning

confidence: 64%

Section: Cdc25b Overexpression Drives Centrosome Overduplicationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation

2007

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“…The cells were then fixed with 100% methanol. Spindle integrity was examined using dual-label immunofluorescence for tubulin and centrin to detect the mitotic spindle and the centrosomes following methods described previously [25]. Primary antibodies were rabbit anti-beta tubulin (Abcam, La Jolla, CA, USA) and mouse anti-centrin (Salisbury Laboratory).…”

Section: Mitotic Spindle and Centrosome Morphology Analysismentioning

confidence: 99%

“…Exposure of rodents to the larger diameter MWCNT (11.3 nm) results in micronuclei in Type II epithelial cells indicating either a high level of chromosomal breakage or mitotic spindle disruption [2]. The integrity of the mitotic spindle and chromosome number are critical because mitotic spindle disruption, centrosome damage and aneuploidy may lead to a greater risk of cancer [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Single-walled carbon nanotube-induced mitotic disruption

Sargent

Hubbs

Young

et al. 2012

Mutation Research/Genetic Toxicology and Environmental Mutagene

147

123

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Carbon nanotubes were among the earliest products of nanotechnology and have many potential applications in medicine, electronics, and manufacturing. The low density, small size, and biological persistence of carbon nanotubes create challenges for exposure control and monitoring and make respiratory exposures to workers likely. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to 24, 48 and 96 μg/cm 2 single-walled carbon nanotubes (SWCNT). To investigate mitotic spindle aberrations at concentrations anticipated in exposed workers, primary and immortalized human airway epithelial cells were exposed to SWCNT for 24-72 h at doses equivalent to 20 weeks of exposure at the Permissible Exposure Limit for particulates not otherwise regulated. We have now demonstrated fragmented centrosomes, disrupted mitotic spindles and aneuploid chromosome number at those doses. The data further demonstrated multipolar mitotic spindles comprised 95% of the disrupted mitoses. The increased multipolar mitotic spindles were associated with an increased number of cells in the G2 phase of mitosis, indicating a mitotic checkpoint response. Nanotubes were observed in association with mitotic spindle microtubules, the centrosomes and condensed chromatin in cells exposed to 0.024, 0.24, 2.4 and 24 μg/cm 2 SWCNT. Three- Conflict of interest statementThe authors declare that there are no conflicts of interest. Appendix A. Supplementary dataSupplementary data associated with this article can be found, in the online version, at doi:10.1016/j.mrgentox.2011.11.017. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript dimensional reconstructions showed carbon nanotubes within the centrosome structure. The lower doses did not cause cytotoxicity or reduction in colony formation after 24 h; however, after three days, significant cytotoxicity was observed in the SWCNT-exposed cells. Colony formation assays showed an increased proliferation seven days after exposure. Our results show significant disruption of the mitotic spindle by SWCNT at occupationally relevant doses. The increased proliferation that was observed in carbon nanotube-exposed cells indicates a greater potential to pass the genetic damage to daughter cells. Disruption of the centrosome is common in many solid tumors including lung cancer. The resulting aneuploidy is an early event in the progression of many cancers, suggesting that it may play a role in both tumorigenesis and tumor progression. These results suggest caution should be used in the handling and processing of carbon nanotubes.

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Induction of aneuploidy by single‐walled carbon nanotubes

Sargent

Shvedova

Hubbs

et al. 2009

Environ and Mol Mutagen

154

152

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Engineered carbon nanotubes are newly emerging manufactured particles with potential applications in electronics, computers, aerospace, and medicine. The low density and small size of these biologically persistent particles makes respiratory exposures to workers likely during the production or use of commercial products. The narrow diameter and great length of single-walled carbon nanotubes (SWCNT) suggest the potential to interact with critical biological structures. To examine the potential of nanotubes to induce genetic damage in normal lung cells, cultured primary and immortalized human airway epithelial cells were exposed to SWCNT or a positive control, vanadium pentoxide. After 24 hr of exposure to either SWCNT or vanadium pentoxide, fragmented centrosomes, multiple mitotic spindle poles, anaphase bridges, and aneuploid chromosome number were observed. Confocal microscopy demonstrated nanotubes within the nucleus that were in association with cellular and mitotic tubulin as well as the chromatin. Our results are the first to report disruption of the mitotic spindle by SWCNT. The nanotube bundles are similar to the size of microtubules that form the mitotic spindle and may be incorporated into the mitotic spindle apparatus.

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Centrosome Amplification and the Origin of Chromosomal Instability in Breast Cancer

Cited by 23 publications

References 82 publications

CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation

CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation

Single-walled carbon nanotube-induced mitotic disruption

Induction of aneuploidy by single‐walled carbon nanotubes

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