DNA double-strand breaks, p53, and apoptosis during lymphomagenesis in scid/scid mice.
The tumor-suppressing phenotype of p53 is thought to be due to its accumulation in response to DNA damage and resultant cell cycle arrest or apoptosis. scid/scid mice are defective in DNA double-strand break repair due to a mutation in DNA-dependent protein kinase (DNAPK). Treatment of scid/scid mice with gamma radiation or N-ethyl-N-nitrosourea resulted in approximately 86% incidence of T-cell lymphomas, compared with <6% in wild-type mice. The incidence of other tumor types was not increased in scid/scid mice, suggesting that the types of DNA double-strand break that are unrepaired in these mice are not strongly carcinogenic. To determine whether mutations in DNAPK and p53 interact, we examined mice deficient in both genes. Both scid/scid p53-/- and scid/scid p53+/- mice spontaneously developed lymphomas at shorter latency than did mice with either defect alone. Loss of the wild-type p53 allele was observed in 100% of tumors from scid/scid p53 +/- mice, indicating strong selection against p53. In contrast, p53 was not inactivated in lymphomas from scid/scid p53+/+ mice. Exposure of these tumor-bearing mice to gamma radiation resulted in p53 protein accumulation and high levels of apoptosis in all tumors that were not observed in tumors from scid/scid p53+/- mice. Thus, there was a bifurcation of molecular pathways to tumorigenesis. When p53 was heterozygous in the germ line, loss of the wild-type allele occurred, and the tumors became apoptosis resistant. When p53 was wild type in the germ line, p53 was not inactivated, and the tumors remained highly apoptosis sensitive.
Gurley
K E
KE
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Vo
K
K
Kemp
C J
CJ
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002273:Carcinogens; D004249:DNA Damage; D005038:Ethylnitrosourea; D005720:Gamma Rays; D016393:Lymphoma, B-Cell / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000528:radiation effects
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D005038:Ethylnitrosourea