Thymocyte apoptosis induced by p53-dependent and independent pathways

Nature. 1993 Apr 29;362(6423):849-52. doi: 10.1038/362849a0.


Death by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy. Apoptosis can be initiated by various agents 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 Ca(2+)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cells, Cultured
  • DNA / drug effects
  • Etoposide / pharmacology
  • Female
  • Gamma Rays
  • Gene Deletion
  • Genes, p53 / physiology*
  • Heterozygote
  • Homozygote
  • Ionomycin / pharmacology
  • Male
  • Methylprednisolone / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Tetradecanoylphorbol Acetate / pharmacology
  • Thymus Gland / cytology*
  • Thymus Gland / drug effects
  • Thymus Gland / radiation effects


  • Ionomycin
  • Etoposide
  • DNA
  • Tetradecanoylphorbol Acetate
  • Methylprednisolone