A model for p53-induced apoptosis


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.


  1. 1

    Waldman, T., Kinzler, K. W. & Vogelstein, B. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res. 55, 5187–5190 (1995).

    CAS  PubMed  Google Scholar 

  2. 2

    Oren, M. Relationship of p53 to the control of apoptotic cell death. Semin. Cancer Biol. 5, 221–227 (1994).

    CAS  PubMed  Google Scholar 

  3. 3

    Velculescu, V. E., Zhang, L., Vogelstein, B. & Kinzler, K. W. Serial analysis of gene expression. Science 270, 484–487 (1995).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Polyak, K., Walkman, T., He, T.-C., Kinzler, K. W. & Vogelstein, B. Genetic determinants of p53 induced apoptosis and growth arrest. Genes Dev. 10, 1945–1952 (1966).

    Article  Google Scholar 

  5. 5

    Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Lehar, S. M.et al. Identification and cloning of Ei24, a gene induced by p53 in etoposide-treated cells. Oncogene 12, 1181–1187 (1996).

    CAS  PubMed  Google Scholar 

  7. 7

    Hayward, D. C.et al. The sluggish-A gene of Drosophila melanogaster is expressed in the nervous system and encodes proline oxidase, a mitochondrial enzyme involved in glutamate biosynthesis. Proc. Natl Acad. Sci. USA 90, 2979–2983 (1993).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Russo, T.et al. Ap53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. J. Biol. Chem. 270, 29386–29391 (1995).

    CAS  Article  Google Scholar 

  9. 9

    Reinhoff, H. Y. J, Huang, J. H., Li, X. X. & Liao, W. S. Molecular and cellular biology of serum amyloid A. Mol. Biol. Med. 7, 287–298 (1990).

    Google Scholar 

  10. 10

    Yamaoka, A., Kuwabara, I., Frigeri, I. G. & Liu, F. T. Ahuman lectin, galectin-3 (epsilon bp/Mac-2) stimulates superoxide production by neutrophils. J. Immunol. 154, 3479–3487 (1995).

    CAS  PubMed  Google Scholar 

  11. 11

    Greenberg, J. T. Programmed cell death: A way of life for plants. Proc. Natl Acad. Sci. USA 93, 12094–12097 (1996).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Rao, P. V., Krishna, C. M. & Zigler, J. S. J Identification and characterization of the enzymatic activity of zeta-crystallin from guinea PIG lens. A novel NADPH : quinone oxidoreductase. J. Biol. Chem. 267, 96–102 (1992).

    CAS  PubMed  Google Scholar 

  13. 13

    Kroemer, G., Zamzami, N. & Susin, S. A. Mitochondrial control of apoptosis. Immun. Today 18, 45–51 (1997).

    Article  Google Scholar 

  14. 14

    Zamzami, N.et al. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J. Exp. Med. 181, 1661–1672 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Petit, P. X.et al. Alterations in mitochondrial structure and function are early events of dexamethasone-induced thymocyte apoptosis. J. Cell. Biol. 130, 157–167 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Tamm, I. & Sehgal, P. B. Halobenzimidazole ribosides and RNA synthesis of cells and viruses. Adv. Virus Res. 22, 187–258 (1978).

    CAS  Article  Google Scholar 

  17. 17

    Orrenius, S., Nobel, C. S. I., van den Dobbelsteen, D. J., Burkitt, M. J. & Slater, A. F. G. Dithiocarbamates and the redox regulation of cell death. Biochem. Soc. Transact. 24, 1032–1038 (1996).

    CAS  Article  Google Scholar 

  18. 18

    Holland, P. C., Clark, M. G., Bloxham, D. P. & Lardy, H. A. Mechanism of action of the hypoglycemic agent diphenyleneiodonium. J. Biol. Chem. 248, 6050–6056 (1973).

    CAS  PubMed  Google Scholar 

  19. 19

    Korsmeyer, S. J. Regulators of cell death. Trends Genet. 11, 101–105 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Susin, S. A.et al. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J. Exp. Med. 184, 1331–1341 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Yang, J.et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Kluck, R. M., Bossy-Wetzel, E., Green, D. R. & Newmeyer, D. D. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275, 1132–1136 (1997).

    CAS  Article  Google Scholar 

  23. 23

    Borek, C. Radiation and chemically induced transformation: free radicals, antioxidants and cancer. Br. J. Cancer suppl. 8, 74–86 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Vayssiere, J. L., Petit, P. X., Risler, Y. & Mignotte, B. Commitment to apoptosis is associated with changes in mitochondrial biogenesis and activity in cell lines conditionally immortalized with simian virus 40. Proc. Natl Acad. Sci. USA 91, 11752–11756 (1994).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Johnson, T. M., Yu, Z.-X., Ferrans, V. J., Lowenstein, R. A. & Finkel, T. Reactive oxygen species are downstream mediators of p53-dependent apoptosis. Proc. Natl Acad. Sci. USA 93, 11848–11852 (1996).

    ADS  CAS  Article  Google Scholar 

  26. 26

    El-Diery, W. S.et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

    Article  Google Scholar 

  27. 27

    Velculescu, V. E.et al. Characterization of the yeast transcriptome. Cell 88, 243–251 (1997).

    CAS  Article  Google Scholar 

  28. 28

    El-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992).

    CAS  Article  Google Scholar 

  29. 29

    Faulkner, K. & Fridovich, I. Luminol and lucigenin as detectors for O−2. Free Rad. Biol. Med. 15, 447–451 (1993).

    CAS  Article  Google Scholar 

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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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