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Thymocyte apoptosis induced by p53-dependent and independent pathways

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Abstract

DEATH by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy1. Apoptosis can be initiated by various agents1–5 and may be a result of expression of the oncosuppressor gene p53 (refs 6–8). Here we study the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca2+-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time-dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Our results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage.

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Author notes

  1. C. A. Purdie

    Present address: Department of Pathology, University of Glasgow, Western Infirmary, Glasgow, G11 6NT, UK

Authors and Affiliations

  1. Cancer Research Campaign Laboratories, Department of Pathology, University Medical School, Teviot Place, Edinburgh, EH8 9AG, UK

    A. R. Clarke, C. A. Purdie, D. J. Harrison, R. G. Morris, C. C. Bird, M. L. Hooper & A. H. Wyllie

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  1. A. R. Clarke
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  2. C. A. Purdie
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  3. D. J. Harrison
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  4. R. G. Morris
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  5. C. C. Bird
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  6. M. L. Hooper
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  7. A. H. Wyllie
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Clarke, A., Purdie, C., Harrison, D. et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362, 849–852 (1993). https://doi.org/10.1038/362849a0

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  • DOI: https://doi.org/10.1038/362849a0

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