DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2.
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.
Strasser
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A
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Harris
A W
AW
Jacks
T
T
Cory
S
S
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays; D016399:Lymphoma, T-Cell / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone