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

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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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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Correspondence to J. Carl Barrett.

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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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