Failure of cell cleavage induces senescence in tetraploid primary cells.
Bottom Line: Tetraploid primary cells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of the fluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin.Arrested tetraploid cells finally become senescent, as determined by SA-β-galactosidase activity.Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypasses tetraploid arrest, permitting primary cells to become aneuploid.
Affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.Show MeSH
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Mentions: To demonstrate a dual requirement for p53 and p16INK4a in the induction of senescence by tetraploidy, we assayed p53-competent HCT116 colon carcinoma cells. We found that HCT116 did not arrest when made tetraploid but continued first to 8N and then to aneuploidy (Figure 9A). In fact, p53+/+ HCT116 colon carcinoma cells continued to proliferate at the same pace as p53−/− HCT116 (Figure 9B). In contrast, exposure of the same cells to the DNA damage agent Adriamycin effectively blocked proliferation. Of importance, although HCT116 cells express wild-type p53, they do not express p16INK4a (Myohanen et al., 1998). These results indicate that expression of intact p53 is not sufficient to induce arrest in tetraploid cells.
Affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.