A model for p53-induced apoptosis

Abstract

The inactivation of the p53 gene in a large proportion of human cancers has inspired an intense search for the encoded protein's physiological and biological properties. Expression of p53 induces either a stable growth arrest or programmed cell death (apoptosis). In human colorectal cancers, the growth arrest is dependent on the transcriptional induction of the protein p21WAF1/CIP1(ref. 1), but the mechanisms underlying the development of p53-dependent apoptosis are largely unknown2. As the most well documented biochemical property of p53 is its ability to activate transcription of genes, we examined in detail the transcripts induced by p53 expression before the onset of apoptosis. Of 7,202 transcripts identified, only 14 (0.19%) were found to be markedly increased in p53-expressing cells compared with control cells. Strikingly, many of these genes were predicted to encode proteins that could generate or respond to oxidative stress, including one that is implicated in apoptosis in plant meristems. These observations stimulated additional biochemical and pharmacological experiments suggesting that p53 results in apoptosis through a three-step process: (1) the transcriptional induction of redox-related genes; (2) the formation of reactive oxygen species; and (3) the oxidative degradation of mitochondrial components, culminating in cell death.

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Figure 1: Summary of SAGE data.
Figure 2: The PIG3 gene, illustrating intron–exon structure and promoter region.
Figure 3: Sequences of selected genes identified through SAGE.
Figure 4: Oxidative stress and mitochondrial damage in p53-mediated apoptosis.

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Acknowledgements

We thank V. Velculescu, L. Zhang and W. Zhou for help with SAGE analysis; J. A. Duine for bongkrekic acid; J. Flook for assistance with flow cytometry; and members of our laboratories for discussion. This work was supported by the Clayton Fund and by grants from the NIH. K.P. is a research associate and B.V. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Kornelia Polyak.

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Polyak, K., Xia, Y., Zweier, J. et al. A model for p53-induced apoptosis. Nature 389, 300–305 (1997). https://doi.org/10.1038/38525

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