Metaphase Micronuclei Multinucleation

Figure 17.3 MiaPaCa2 pancreatic cancer cells after 10 Gy radiation showing abnormal mitosis (metaphase) with multiple centrosomes (green, pericentrin labeling) dispersed chaotically throughout the condensed chromosomes (A), followed by the appearance of the micro- (B) and multinucleated (C) phenotype, characteristic of mitotic cell death (see Color Plates page XXXVIII).

Figure 17.3 MiaPaCa2 pancreatic cancer cells after 10 Gy radiation showing abnormal mitosis (metaphase) with multiple centrosomes (green, pericentrin labeling) dispersed chaotically throughout the condensed chromosomes (A), followed by the appearance of the micro- (B) and multinucleated (C) phenotype, characteristic of mitotic cell death (see Color Plates page XXXVIII).

apoptosis [75]. These authors have also shown that calmodulin-dependent protein kinase II (CaMKII), which is known to be associated with centrosomes [76, 77], is involved in apoptosis induced by ionizing radiation. We have observed that a subset of irradiated cells with multiple centrosomes appear to undergo apoptosis as determined by TUNEL staining [27]. Bunz and coworkers also noted apoptotic cell death after y-radiation in a subset of p53—/— or p21—/— cells containing multiple centrosomes [41]. These studies, however, did not establish causality between centro-some defects and apoptosis. It is also possible that nuclear fragmentation associated with centrosome anomalies could trigger apoptosis. Merritt and colleagues described a p53-independent delayed apoptosis in small intestinal epithelia after irradiation, which was associated with the appearance of giant cells with fragments of condensed chromatin in their nucleus [78]. In addition, several investigators have shown that p53 protein is upregulated in micronucleated cells, thereby directing these cells toward apoptosis [79 ,80]. Together, these observations raise the possibility that numerical aberrations of centrosomes and/or the resulting nuclear fragmentation may be critical events leading to apoptosis in irradiated cells. The final determination of whether cells with multiple centrosomes die by apoptosis or mitotic death may depend on the integrity of the checkpoint and/or apoptotic pathways.

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