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Involvement of p85 in p53-dependent apoptotic response to oxidative stress

Nature volume 391, pages 707–710 (1998)Cite this article

Abstract

Reactive oxygen species have damaging effects on cellular components and so trigger defensive responses by the cell1,2 and even programmed cell death3,4, although the mechanisms by which mammalian cells transmit signals in response to oxidative damage are unknown. We report here that the protein p85, a regulator of the signalling protein phosphatidyl-3-OH kinase (PI(3)K), participates in the cell death process that is induced in response to oxidative stress and that this role of p85 in apoptosis does not involve PI(3)K. We show that disruption of p85 by homologous recombination impairs the cellular apoptotic response to oxidative stress. Because the protein p53 is required for cell death induced by oxidative damage, we examined the relation between p85 and p53. Using a chimaeric p53 fusion protein with the oestrogen receptor (p53ER) to supply p53 (p53 is induced upon binding of p53ER to oestradiol) in a p53-deficient cell line, we found that p85 is upregulated by p53 and that its involvement in p53-mediated apoptosis is independent of PI(3)K. We propose that p85 acts as a signal transducer in the cellular response to oxidative stress, mediating cell death regulated by p53.

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Figure 1: Involvement of p85 in the cellular response to oxidative stress in a manner independent of PI(3)K.
Figure 2: Morphology of p85 MEFs in various conditions.
Figure 3: A p53ER inducible system in a p53-deficient human lung-cancer cell line.
Figure 4: Regulation of p85 in a p53-dependent manner.
Figure 5: Inhibition of p85 expression and apoptosis in p53ER cells by p85 antisense technology.

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References

  1. Bagchi, D., Bagchi, M., Hassoun, E. A. & Stohs, S. J. In vitro and in vivo generation of reactive oxygen species, DNA damage and lactate dehydrogenase leakage by selected pesticides. Toxicology 104, 129–140 (1995).

    Article  CAS  Google Scholar 

  2. Storz, G., Tartaglia, L. A., Farr, S. B. & Ames, B. N. Bacterial defences against oxidative stress. Trends Genet. 6, 363–368 (1990).

    Article  CAS  Google Scholar 

  3. Hockenbery, D. M., Oltvai, Z. N., Yin, X. M., Milliman, C. L. & Korsmeyer, S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75, 241–251 (1993).

    Article  CAS  Google Scholar 

  4. Korsmeyer, S. J., Yin, X. M., Oltvai, Z. N., Veis Novack, D. J. & Linette, G. P. Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family. Biochim. Biophys. Acta 1271, 63–66 (1995).

    Article  Google Scholar 

  5. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    Article  ADS  CAS  Google Scholar 

  6. Hu, P. et al. Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mol. Cell. Biol. 12, 981–990 (1992).

    Article  CAS  Google Scholar 

  7. Carpenter, C. L. & Cantley, L. C. Phosphoinositide kinases. Curr. Opin. Cell Biol. 8, 153–158 (1996).

    Article  CAS  Google Scholar 

  8. Pleiman, C. M., Hertz, W. M. & Cambier, J. C. Activation of phosphatidylinositol-3′ kinase by Src-family kinase SH3 binding to the p85 subunit. Science 263, 1609–1612 (1994).

    Article  ADS  CAS  Google Scholar 

  9. Arcaro, A. & Wymann, M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297–301 (1993).

    Article  CAS  Google Scholar 

  10. Ferby, I. M., Waga, I., Hoshino, M., Kume, K. & Shimizu, T. Wortmannin inhibits mitogen-activated protein kinase activation by platelet-activating factor through a mechanism independent of p85/p110-type phosphatidylinositol 3-kinase. J. Biol. Chem. 271, 11684–11688 (1996).

    Article  CAS  Google Scholar 

  11. Baker, S. J., Markowitz, S., Fearon, E. R., Willson, J. K. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).

    Article  ADS  CAS  Google Scholar 

  12. Kern, S. E. et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827–830 (1992).

    Article  ADS  CAS  Google Scholar 

  13. Otsu, M. et al. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell 65, 91–104 (1991).

    Article  CAS  Google Scholar 

  14. Kotani, K., Hara, K., Kotani, K., Yonezawa, K. & Kasuga, M. Phosphoinositide 3-kinase as an upstream regulator of the small GTP-bindign protein Rac in the insulin signaling of membrane ruffling. Biochem. Biophys. Res. Commun. 208, 985–990 (1995).

    Article  CAS  Google Scholar 

  15. Kapeller, R. & Cantley, L. C. Phosphatidylinositol 3-kinase. Bioessays 16, 565–576 (1994).

    Article  CAS  Google Scholar 

  16. Backer, J. M. et al. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 11, 3469–3479 (1992).

    Article  CAS  Google Scholar 

  17. Carpenter, C. L. & Cantley, L. C. Phosphoinositide 3-kinase and the regulation of cell growth. Biochim. Biophys. Acta 1288, 11–16 (1996).

    Google Scholar 

  18. Yao, R. & Cooper, G. M. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267, 2003–2006 (1995).

    Article  ADS  CAS  Google Scholar 

  19. Kauffmann-Zeh, A. et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385, 544–548 (1997).

    Article  ADS  CAS  Google Scholar 

  20. Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W. & Vogelstein, B. Amodel for p53-induced apoptosis. Nature 389, 300–305 (1997).

    Article  ADS  CAS  Google Scholar 

  21. Tamemoto, H. et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186 (1994).

    Article  ADS  CAS  Google Scholar 

  22. Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual2nd edn (Cold Spring Harbor Laboratory Press, NY, (1989)).

    Google Scholar 

  25. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & Wahl, G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).

    Article  CAS  Google Scholar 

  26. Preston, G. A. et al. Induction of apoptosis by c-Fos protein. Mol. Cell. Biol. 16, 211–218 (1996).

    Article  CAS  Google Scholar 

  27. Hartley, D., Meisner, H. & Corvera, S. Specific association of the beta isoform of the p85 subunit of phosphatidylinositol-3 kinase with the proto-oncogene c-cbl. J. Biol. Chem. 270, 18260–18263 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Vogelstein for the plasmid PG13CAT; D. Carbone for H1299 cell line; A.Bradley for p53 MEFs; L. T. Williams and E. Y. Skolnik for p85 cDNAs; G. M. Wahl and T. A. Van Dyke for input and advice; G. A. Preston for DNA ladder analysis; J. E. Stenger for critical comments on themanuscript; and S. Sandberg for help with the manuscript. Y. Yin is grateful to T. D. Tisty and S. T. Lord for their support. This work was supported in part by a Grant-in-Aid for the second term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan (to Y.Y.). Y. Yin was supported by an NIH training fellowship at the University of North Carolina.

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Author notes

  1. Yuxin Yin

    Present address: Department of Molecular Biology, Princeton University, Princeton, New Jersey, 08544, USA

Authors and Affiliations

  1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, 27709, USA

    Yuxin Yin, Gregory G. Solomon & J. Carl Barrett

  2. Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Yuxin Yin & J. Carl Barrett

  3. Third Department of Internal Medicine, University of Tokyo, Tokyo, 113, Japan

    Yasuo Terauchi, Yoshio Yazaki & Takashi Kadowaki

  4. Laboratory of Morphogenesis, Kumamoto University Medical School, Kumamoto, 860, Japan

    Shinichi Aizawa

  5. Department of Biochemistry, Indian Institute of Science, Bangalor, 560012, India

    P. N. Rangarajan

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Yin, Y., Terauchi, Y., Solomon, G. et al. Involvement of p85 in p53-dependent apoptotic response to oxidative stress. Nature 391, 707–710 (1998). https://doi.org/10.1038/35648

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