Centrosomal amplification and aneuploidy induced by the antiretroviral drug AZT in hamster and human cells
| Autor: | Catherine Cooch, Ofelia A. Olivero, Mia Yu, Jessica M. Ming, Jennifer P. Borojerdi, Barbara J. Taylor, Hannan M. Braun, Yvona Ward, Miriam C. Poirier, Cristina Semino-Mora |
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| Rok vydání: | 2009 |
| Předmět: |
Genome instability
Health Toxicology and Mutagenesis Aurora B kinase Hamster CHO Cells Protein Serine-Threonine Kinases Article Cell Line DNA Adducts Cricetulus Microscopy Electron Transmission Aurora Kinases Tubulin Cricetinae Genetics Animals Humans Breast Molecular Biology Micronuclei Chromosome-Defective Centrosome biology Chinese hamster ovary cell Cell Cycle Epithelial Cells Cell cycle Aneugens Aneuploidy Molecular biology Cell biology Cell culture biology.protein Zidovudine |
| Zdroj: | Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 665:67-74 |
| ISSN: | 0027-5107 |
| DOI: | 10.1016/j.mrfmmm.2009.03.004 |
| Popis: | The centrosome directs chromosomal migration by a complex process of tubulin-chromatin binding. In this contribution centrosomal abnormalities, including centrosomal amplification, were explored in Chinese hamster ovary (CHO) and normal human mammary epithelial cells (NHMECs) exposed to the antiretroviral drug zidovudine (3'-azido-3'-deoxythymidine, AZT). Centrosomal amplification/fragmentation was observed in both cell types and kinetochore positive micronuclei were found in AZT-exposed CHO cells in correlation with dose. Normal human mammary epithelial cell (NMHEC) strain M99005, previously identified as a strain that incorporates high levels of AZT into DNA (high incorporator, HI), showed greater centrosomal amplification when compared with a second strain, NHMEC M98040, which did not incorporate AZT into DNA (low incorporator, LI). Additionally, an abnormal tubulin distribution was observed in AZT-exposed HI cells bearing multiple centrosomes. Immunofluorescent staining of human cells with Aurora A, a kinase involved in the maturation of the centrosome, confirmed the induction of centrosomal amplification and revealed multipolar mitotic figures. Flow cytometric studies revealed that cells bearing abnormal numbers of centrosomes and abnormal tubulin distribution had similar S-phase percentages suggesting that cells bearing unbalanced chromosomal segregation could divide. Therefore, AZT induces genomic instability and clastogenicity as well as alterations in proteins involved in centrosomal activation, all of which may contribute to the carcinogenic properties of this compound. |
| Databáze: | OpenAIRE |
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