Oncogene, 2004-05, Vol.23 (25), p.4362-4370
2004
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- Autor(en) / Beteiligte
- Titel
- Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy
- Ist Teil von
- Oncogene, 2004-05, Vol.23 (25), p.4362-4370
- Ort / Verlag
- Basingstoke: Nature Publishing
- Erscheinungsjahr
- 2004
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- A conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe when the DNA structure checkpoints are inactivated, for instance when the checkpoint kinase Chk2 is inhibited. Here we show that in such conditions, cells die during the metaphase of the cell cycle, as a result of caspase activation and subsequent mitochondrial damage. Molecular ordering of these phenomena reveals that mitotic catastrophe occurs in a p53-independent manner and involves a primary activation of caspase-2, upstream of cytochrome c release, followed by caspase-3 activation and chromatin condensation. Suppression of caspase-2 by RNA interference or pseudosubstrate inhibitors as well as blockade of the mitochondrial membrane permeabilization prevent the mitotic catastrophe and allow cells to further proceed the cell cycle beyond the metaphase, leading to asymmetric cell division. Heterokarya generated by the fusion of nonsynchronized cells can be driven to divide into three or more daughter cells when Chk2 and caspases are simultaneously inhibited. Such multipolar divisions, resulting from suppressed mitotic catastrophe, lead to the asymmetric distribution of cytoplasm (anisocytosis), DNA (anisokaryosis) and chromosomes (aneuploidy). Similarly, in a model of DNA damage-induced mitotic catastrophe, suppression of apoptosis leads to the generation of aneuploid cells. Our findings delineate a molecular pathway through which DNA damage, failure to arrest the cell cycle and inhibition of apoptosis can favor the occurrence of cytogenetic abnormalities that are likely to participate in oncogenesis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/sj.onc.1207572Titel-ID: cdi_proquest_miscellaneous_71997615
- Format
- –
- Schlagworte
- Ageing, cell death, Amino Acid Chloromethyl Ketones - pharmacology, Aneuploidy, Antibiotics, Antineoplastic - pharmacology, Apoptosis, Apoptosis - genetics, Apoptosis - physiology, Azepines - pharmacology, Biological and medical sciences, Caspase 2, Caspase 3, Caspase Inhibitors, Caspases - physiology, CD4 Antigens - genetics, Cell cycle, Cell death, Cell Division, Cell Fusion, Cell Line, Tumor - drug effects, Cell physiology, Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes, Cell Transformation, Neoplastic, Centrosome - physiology, Centrosome - ultrastructure, Checkpoint Kinase 2, CHK2 protein, Chromatin, Chromosome aberrations, Chromosomes, Colonic Neoplasms - pathology, Cysteine Proteinase Inhibitors - pharmacology, Cytochrome, Cytochrome c, Cytogenetics, Cytoplasm, Deoxyribonucleic acid, DNA, DNA Damage, DNA structure, Doxorubicin - pharmacology, Fundamental and applied biological sciences. Psychology, Genes, env, Giant Cells - cytology, Giant Cells - drug effects, Giant Cells - enzymology, HeLa Cells - cytology, HeLa Cells - enzymology, Humans, Intracellular Membranes - drug effects, Intracellular Membranes - physiology, Kinases, Medical genetics, Medical sciences, Metaphase, Mitochondria, Mitochondria - physiology, Mitochondria - ultrastructure, Mitosis - genetics, Models, Biological, Molecular and cellular biology, p53 Protein, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Protein-Serine-Threonine Kinases - physiology, Pyrroles - pharmacology, RNA Interference, RNA-mediated interference, Transfection, Tumorigenesis