Abstract
The topoisomerase I inhibitor SN38 arrests cell cycle progression primarily in S or G2 phases of the cell cycle in a p53-independent manner. The Chk1 inhibitor, 7-hydroxystaurosporine (UCN-01), overcomes both S and G2 arrest preferentially in cells mutated for p53, driving cells through a lethal mitosis and thereby enhancing cytotoxicity. The mechanism by which p53 maintains S and G2 arrest was investigated here. The p53 wild-type MCF10A cells were arrested in S phase by incubation with SN38 for 24 h. Subsequent incubation with UCN-01 failed to abrogate arrest. To examine the impact of p53, MCF10A cells were developed, which express the tetramerization domain of p53 to inhibit endogenous p53 function. These cells were attenuated in SN38-mediated induction of p21WAF1 and UCN-01 induced S, but not G2 progression. In contrast, MCF10A cells expressing short hairpin RNA to ablate p53 expression underwent both S and G2 phase progression with UCN-01. The difference in G2 progression was attributed to p53-mediated gene repression; the MCF10A cells expressing the tetramerization domain retained p53 protein and repressed both cyclin B and Chk1, while cells ablated for p53 did not repress these proteins. Hence, inhibition of p53 activator function permits S phase abrogation, while additional inhibition of p53 repressor function is required for abrogation of G2 arrest. These studies provide a mechanistic explanation for how this therapeutic strategy can selectively target tumor cells.
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Acknowledgements
We thank Mark Livingstone, Cell Signaling, for consultation and early access to many of the phospho-specific antibodies used. This work was supported by National Institutes of Health Grant CA82220 and a Cancer Center Support Grant CA23108 to the Norris Cotton Cancer Center. AAL was supported by a National Institutes of Health training Grant T3209658. EAK was supported by a fellowship from the Susan G Komen Breast Cancer Foundation.
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Levesque, A., Kohn, E., Bresnick, E. et al. Distinct roles for p53 transactivation and repression in preventing UCN-01-mediated abrogation of DNA damage-induced arrest at S and G2 cell cycle checkpoints. Oncogene 24, 3786–3796 (2005). https://doi.org/10.1038/sj.onc.1208451
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DOI: https://doi.org/10.1038/sj.onc.1208451
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