DNA-DAMAGING AGENTS INDUCE BOTH P53-DEPENDENT AND P53-INDEPENDENT APOPTOSIS IN IMMATURE THYMOCYTES

Apoptosis in the immature thymus can be induced by both p53-dependent and -independent pathways, the former being activated by exposure to D NA-damaging agents and the latter being induced by glucocorticoids [Na ture (Lond.) 362:847-849; Nature (Lond.) 362:849-852 (1993)]. We repor t that the DNA-damaging agents etoposide and gamma-radiation induced s imilar levels of apoptosis in both proliferatively enriched and quiesc ent immature rat thymocytes, as assessed by flow cytometry and the for mation of both kilobase-pair and 180-bp integer fragments of DNA. Howe ver, a marked stabilization of p53 occurred exclusively in the prolife ratively 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 a ssociated with an accumulation of p53. Our studies suggest that stabil ization of p53 in thymocytes in response to DNA damage may be developm entally regulated. In immature thymocytes obtained from p53-null mice, DNA-damaging agents induced apoptosis at significantly lower levels a nd at later times than that seen in cells from p53 wild-type animals. These data support the hypothesis that DNA-damaging agents induce apop tosis primarily via a p53-dependent pathway in immature thymocytes as previously reported. We report here that DNA damage can also induce ap optosis by a p53-independent pathway in a particular subpopulation of immature thymocytes.