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Effect of p21waf1/cip1 transgene on radiation induced apoptosis in T cells

Oncogene volume 18, pages 3652–3658 (1999)Cite this article

Abstract

The cyclin kinase inhibitor p21WAF1/Cip1 is upregulated by the tumor suppressor p53. While p21 is central for the G-1 arrest mediated by p53, it is still unclear if p21 also functions as a downstream effector of p53 dependent apoptosis. Apoptosis induced by DNA damage but not dexamethasone is p53 dependent in thymocytes. To investigate the physiological role of p21 in apoptosis, we have generated transgenic mice in which the p21 transgene is targeted for restricted expression in the T cell lineage. Thymocytes from p21 transgenic mice were hypersensitive to cell death induced by DNA damaging agents such as ionizing radiation and UV, but not be dexamethasone. Irradiated p21 transgenic thymocytes had approximately twofold more apoptotic cells as compared to irradiated age matched littermate control mice. Radiation induced death is comparable in thymocytes from p21+Bcl2+double transgenic mice and age matched littermate controls, indicating that the Bcl2 transgene rescues the radiation hypersensitivity imposed by p21. However, thymocytes from p53−/− mice even when they expressed the p21 transgene, were resistant to death induced by radiation. Together these results show that thymocytes from p21 transgenic mice are hypersensitive to radiation induced programmed cell death and suggest that the radiation hypersensitivity of p21 transgenic thymocytes involves p53 dependent pathway and signals in addition to p21.

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Acknowledgements

We acknowledge the generous gift of p53 null mice by Tyler Jacks (Massachusetts Institute of Technology) and the p1017 transgenic vector by R Perlmutter (University of Washington). The authors acknowledge H Messier for cloning p21, J Price for oocyte microinjections, and P Linton for purifying splenic T and B cells. The authors also acknowledge the dedicated technical help by V Barbier, V Marrell and P Fitzgerald. A Fotedar thanks T Hunter for a helpful discussion. We thank Dr R Margolis for critically reading this manuscript. T Rousselle and L Diederich were supported by a studentship and a fellowship respectively from Region Rhône Alpes. This work was supported by grants to R Fotedar from the Region Rhône Alpes [HO9873.08.12], and l'Association pour la Recherche sur le Cancer [6675] and by grants to A Fotedar from the American Cancer Society [DB107] and the National Institutes of Health [AI31453 and CA74435].

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Authors and Affiliations

  1. Institut de Biologie Structurale JP Ebel, 41 avenue des Martyrs, 38027, Grenoble, Cedex 1, France

    Rati Fotedar, Tristan Rousselle & Ludger Diederich

  2. Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, 92121, California, USA

    Howard Brickner, Anil Munshi, Barbara Jung & Arun Fotedar

  3. Division of Molecular Biology, La Jolla Institute for Allergy and Immunology, 11149 North Torrey Pines Road, La Jolla, 92037, California, USA

    Howard Brickner, Neshat Saadatmandi & Arun Fotedar

  4. Burnham Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    John C Reed

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  1. Rati Fotedar
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Fotedar, R., Brickner, H., Saadatmandi, N. et al. Effect of p21waf1/cip1 transgene on radiation induced apoptosis in T cells. Oncogene 18, 3652–3658 (1999). https://doi.org/10.1038/sj.onc.1202693

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