High and low fluences of alpha-particles induce a G1 checkpoint in human diploid fibroblasts.
The effects of exposure to high and very low fluence alpha-particles on the G1 checkpoint were investigated in human diploid fibroblasts irradiated and released from density-inhibited confluent cultures by the use of the cumulative labeling index method. Transient and permanent arrests in G1 occurred in fibroblast populations exposed to mean doses as low as 1 cGy, suggesting that nontraversed bystander cells may contribute to the low dose response. In cells exposed to high fluences, the G1 checkpoint is at least as extensive as in gamma-irradiated cells. In contrast to gamma-irradiated cells, neither repair of potentially lethal damage nor a reduction in the fraction of cells transiently or permanently arrested in G1 were observed in cells held in confluence for 6 h after alpha-particle irradiation. Studies with isogenic wild-type, p53-/-, and p21Waf1-/- mouse embryo fibroblasts exposed to either gamma or alpha-particle radiation revealed a total lack of G1 arrest in either p53-/- or p21waf1-/- cells, indicating that the G1 checkpoint in wild-type cells is p53-dependent and that p21Wf1 fully mediates the role of p53 in its induction. In contrast to human cells, mouse embryo fibroblasts do not undergo a permanent G1 arrest. Except under conditions favoring potentially lethal damage repair, a comparable expression pattern of p53, p21Waf1, and other cell cycle-regulated proteins (pRb, p34cdc2, and cyclin B1) was observed in alpha-particle or gamma-irradiated human fibroblasts.
Azzam
E I
EI
Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
de Toledo
S M
SM
Waker
A J
AJ
Little
J B
JB
D000512:Alpha Particles; D000818:Animals; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival; D019926:Cyclin B / Q000096:biosynthesis / Q000528:radiation effects; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000528:radiation effects; D004261:DNA Replication / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects*; D016193:G1 Phase / Q000528:radiation effects*; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D051379:Mice; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects
C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase