Cell

Cell

Volume 79, Issue 2, 21 October 1994, Pages 329-339
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Article
DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2

https://doi.org/10.1016/0092-8674(94)90201-1Get rights and content

Abstract

The roles of p53 as an inducer and Bcl-2 as an inhibitor of apoptotic death were explored in lymphoid cells. Lymphocytes from p53−/− mice were radioresistant, but unexpectedly, cycling T lymphoma cells and mitogenically activated T lymphocytes from these animals underwent apoptosis after irradiation or genotoxic drug treatment. Hence, p53 is not the only mediator of apoptosis provoked by DNA damage. Irradiated p53−/− lymphoblasts expressing Bcl-2 were subject to growth arrest but resisted apoptosis. Their accumulation in G1 as well as G2 is suggestive of a p53-independent DNA-damage G1 checkpoint. Since Bcl-2 increased the clonogenic survival of the irradiated cells, expression of survival genes may pose a greater impediment to genotoxic cancer therapy than loss of p53.

References (72)

  • S.J. Korsmeyer

    Bcl-2 initiates a new category of oncogenes: regulators of cell death

    Blood

    (1992)
  • L.R. Livingstone et al.

    Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53

    Cell

    (1992)
  • J. Lotem et al.

    Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents

    Blood

    (1993)
  • S.W. Lowe et al.

    p53-dependent apoptosis modulates the cytotoxicity of anticancer agents

    Cell

    (1993)
  • D. Michalovitz et al.

    Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53

    Cell

    (1990)
  • M. Miura et al.

    Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3

    Cell

    (1993)
  • I. Nicoletti et al.

    A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry

    J. Immunol. Meth.

    (1991)
  • M. Pettersson et al.

    Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells

    Blood

    (1992)
  • C.L. Sentman et al.

    bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes

    Cell

    (1991)
  • A. Strasser et al.

    Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship

    Cell

    (1991)
  • A.H. Wyllie et al.

    Cell death: the significance of apoptosis

    Int. Rev. Cytol.

    (1980)
  • Y. Yin et al.

    Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles

    Cell

    (1992)
  • J. Yuan et al.

    The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme

    Cell

    (1993)
  • M. Zutter et al.

    Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms

    Blood

    (1991)
  • S.-K. Chiou et al.

    Bcl-2 blocks p53-dependent apoptosis

    Mol. Cell. Biol.

    (1994)
  • A.R. Clarke et al.

    Thymocyte apoptosis induced by p53-dependent and independent pathways

    Nature

    (1993)
  • A.R. Clarke et al.

    p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following γ-irradiation

    Oncogene

    (1994)
  • J.J. Cohen et al.

    Apoptosis and programmed cell death in immunity

    Annu. Rev. Immunol.

    (1992)
  • L. Diller et al.

    p53 functions as a cell cycle control protein in osteosarcomas

    Mol. Cell. Biol.

    (1990)
  • L.A. Donehower et al.

    Mice deficient for p53 are developmentally normal but are susceptible to spontaneous tumours

    Nature

    (1992)
  • M. Egerton et al.

    Kinetics of mature T cell development in the thymus

  • R.E. Ellis et al.

    Mechanisms and functions of cell death

    Annu. Rev. Cell Biol.

    (1991)
  • T.C. Fisher et al.

    bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways

    Cancer Res.

    (1993)
  • M. Fritsche et al.

    Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents

    Oncogene

    (1993)
  • W. Gorczyca et al.

    Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays

    Cancer Res.

    (1993)
  • R.R. Hardy et al.

    Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow

    J. Exp. Med.

    (1991)

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