Cell cycle arrest defect in Li-Fraumeni Syndrome: a mechanism of cancer predisposition?
Cancer predisposition in approximately 60% of Li-Fraumeni Syndrome (LFS) families is associated with germline mutation of the TP53 gene. The p53 protein has been shown to mediate G1 arrest following DNA damage. We have investigated gamma-irradiation-induced transient and permanent G1 arrest in normal and LFS fibroblasts. The duration of transient G1 arrest varied between strains, but there was no difference in the range between normal (2-12 h) and LFS (1-13 h) cells. However, the extent of permanent G1 arrest was greatly reduced in LFS fibroblasts (mean 33+/-8% of the cell population) compared with normals (mean 67+/-9%) and correlated with their increased radiation survival (r=0.97, P<0.001). This phenotype was observed in LFS fibroblasts both with (seven cases) and without (two cases) TP53 mutation. Parallel studies with fibroblasts derived from cancer-prone, p53-deficient mice revealed no radiation-induced G1 cell cycle arrest in p53 null (-/-) cells. The p53 +/- cells were comparable to the wt p53 cells in transient G1 arrest capacity, but showed a diminished permanent G1 arrest. These data clearly implicate p53 function in permanent G1 arrest. The reduced capacity for DNA damage-induced, permanent G1 arrest in LFS may contribute significantly to cancer predisposition in this familial syndrome.
Williams
K J
KJ
CRC Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Boyle
J M
JM
Birch
J M
JM
Norton
J D
JD
Scott
D
D
D000818:Animals; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004198:Disease Susceptibility; D005347:Fibroblasts / Q000528:radiation effects; D016193:G1 Phase / Q000235:genetics / Q000528:radiation effects*; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014410:Tumor Stem Cell Assay
D004273:DNA, Neoplasm