DNA-damaging agents induce both p53-dependent and p53-independent apoptosis in immature thymocytes

Marion Macfarlane, Neil A. Jones, Caroline Dive, Gerald M. Cohen

Research output: Contribution to journalArticlepeer-review

Abstract

Apoptosis in the immature thymus can be induced by both p53-dependent and -independent pathways, the former being activated by exposure to DNA- damaging agents and the latter being induced by glucocorticoids [Nature (Lond.) 362:847-849; Nature (Lond.) 362:849-852 (1993)]. We report that the DNA-damaging agents etoposide and γ-radiation induced similar levels of apoptosis in both proliferatively enriched and quiescent immature rat thymocytes, as assessed by flow cytometry and the formation of both kilobase- pair and 180-bp integer fragments of DNA. However, a marked stabilization of p53 occurred exclusively in the proliferatively enriched population, which was also enriched for immature CD4-CD8- and mature CD4+CD8-/CD4-CD8+ cells. In contrast, DNA damage-induced apoptosis in quiescent mature peripheral T cells was associated with an accumulation of p53. Our studies suggest that stabilization of p53 in thymocytes in response to DNA damage may be developmentally regulated. In immature thymocytes obtained from p53-null mice, DNA-damaging agents induced apoptosis at significantly lower levels and at later times than that seen in cells from p53 wild-type animals. These data support the hypothesis that DNA-damaging agents induce apoptosis primarily via a p53-dependent pathway in immature thymocytes as previously reported. We report here that DNA damage can also induce apoptosis by a p53-independent pathway in a particular subpopulation of immature thymocytes.
Original languageEnglish
Pages (from-to)900-911
Number of pages11
JournalMolecular pharmacology
Volume50
Issue number4
Publication statusPublished - Oct 1996

Keywords

  • Amino Acid Sequence
  • Animals
  • Antigens, CD/analysis
  • Antigens, Differentiation, T-Lymphocyte/analysis
  • Antineoplastic Agents, Phytogenic/*toxicity
  • Apoptosis/drug effects/*physiology/radiation effects
  • Cell Division/physiology
  • DNA/*drug effects/metabolism/*radiation effects
  • *DNA Damage
  • Dexamethasone/toxicity
  • Etoposide/*toxicity
  • *Gamma Rays
  • Male
  • Mice
  • Molecular Sequence Data
  • Proto-Oncogene Proteins/metabolism
  • *Proto-Oncogene Proteins c-bcl-2
  • Rats
  • Rats, Inbred F344
  • T-Lymphocytes/drug effects/physiology/radiation effects
  • Thymus Gland/*cytology/drug effects/radiation effects
  • Tumor Suppressor Protein p53/biosynthesis/*physiology
  • bcl-2-Associated X Protein

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