Neither p21WAF1 nor 14-3-3sigma prevents G2 progression to mitotic catastrophe in human colon carcinoma cells after DNA damage, but p21WAF1 induces stable G1 arrest in resulting tetraploid cells
| Autor: | P R, Andreassen, F B, Lacroix, O D, Lohez, R L, Margolis |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Exonucleases G2 Phase Microscopy Confocal Ploidies Nocodazole Mitosis Proteins Antineoplastic Agents DNA Neoplasm Neoplasm Proteins 14-3-3 Proteins Doxorubicin Cyclins Colonic Neoplasms Exoribonucleases Biomarkers Tumor Mitotic Index Tumor Cells Cultured Humans DNA Damage Etoposide |
| Zdroj: | Cancer research. 61(20) |
| ISSN: | 0008-5472 1584-1588 |
| Popis: | p21WAF1 and 14-3-3sigma, which are both transcriptional products of p53, have been reported to play a role in the G2 DNA damage checkpoint in mammalian cells. Human colon carcinoma cells, isogenic except for the presence or absence of either p21WAF1 or 14-3-3sigma (T. A. Chan et al., Genes Dev., 14: 1584-1588, 2000), are useful models for analysis of the role of these proteins in checkpoint control. Here, we have examined mitotic behavior within a single cell cycle after DNA damage in these cell lines. Our results show that p21WAF1, but not 14-3-3sigma, imposes a significant G2 delay after DNA damage. After G2 delay, we found that all isogenic cells, including those competent for both p21WAF1 and 14-3-3sigma, adapt to the DNA damage checkpoint and progress into mitosis, where they undergo incomplete chromosome segregation and reenter G1 with a tetraploid DNA content. Strikingly, our results show that p21WAF1, but not 14-3-3sigma, activates a checkpoint in response to DNA damage that prevents continued cycling of the tetraploid cells that result from a mitotic catastrophe characterized by failure to complete cell division. These results demonstrate that a tetraploid DNA content is not a reliable criterion to establish that arrest occurs in G2. Also, the DNA damage checkpoint mediated by p53-dependent induction of p21WAF1 assures neither G2 arrest nor DNA repair sufficient to enable accurate chromosome segregation in human colon carcinoma cells. We conclude that p21WAF1, but not 14-3-3sigma, has a unique role in the induction of G1 arrest in tetraploid cells that results from mitotic catastrophe after DNA damage. |
| Databáze: | OpenAIRE |
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