Abstract
In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53[gln22ser23], is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53[gln22ser23]. Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60–90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.
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Acknowledgements
We are grateful to Ella Freulich for expert technical assistance and to Vanessa Gottifredi for critical reading and helpful discussions. This work was supported by grants from the NIH (CA77742) and US Army [17-94—J-4275] to C Prives and from the US Army [DAMD17-94-J-4142 and DAMD17-97-I-7019] to X Chen.
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Baptiste, N., Friedlander, P., Chen, X. et al. The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene 21, 9–21 (2002). https://doi.org/10.1038/sj.onc.1205015
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