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Radiation-induced Gj Arrest Is Selectively Mediated by the p53-WAFl/Cipl Pathway in Human Thyroid Cells1

We investigated the sensitivity and sequential events that take place in thyroid epithelial cells after irradiation. Cell survival ratios at a dose of 2 Gy were 18 Â±2.5%, 58 Â±1.0%, 59 Â±1.5%, and 98 Â±1.8% in primary thyroid cells, papillary thyroid carcinoma cells, follicular thyroid carci noma cells, and anaplastic thyroid carcinoma cells, respectively. Thyroid carcinoma cell lines carrying mutations in the Â¡>5.l gene were resistant to ionizing radiation. Although irradiated cells were accumulated at G, in primary thyroid cells even after low-dose irradiation (0.2 Gy), this phe nomenon was not observed in the thyroid carcinoma cell lines. Wild-type p53 expression in primary thyroid cell was increased following irradia tion, but mutated p53 in the thyroid carcinoma cell lines was unchanged. To clarify the signal transduction in the Gt arrest following irradiation, levels of expression of the p53 putative downstream effectors GADD45 and WAFl/Cipl were examined. Despite the consistent level of GADD45 niRNA. the level of WAFl/Cipl transcripts was increased in a radiation dose-dependent manner in primary thyroid cells. This increase in the WAFl/Cipl mRNA level was observed 30 min after irradiation and continued for at least 48 h. A mobility shift assay performed using the sequence of the putative p53 DNA binding site on the WAFl/Cipl and GADD45 genes as a probe showed that nuclear protein extracted from primary thyroid cells, anti-p53 antibody, and probe oligonucleotidebound complex was clearly shifted. An increase in binding activity of the p53/antibody/DNA complex was observed following irradiation. In con trast, the nuclear extract from thyroid carcinoma cells could not bind the specific DNA site, suggesting that mutant p53 has lost its binding ability. Actinomycin D inhibited WAFl/Cipl and GADD45 mRNA levels and cycloheximide stimulated up-regulation of both basal mRNA levels, but an additional increase of the mRNA expression following irradiation was observed only in the WAFl/Cipl gene. These data suggest that p53 in postradiation acts at a transcriptional level on WAFl/Cipl gene expression and that Â¡lenovo protein synthesis is not required for this effect. These results suggest that the p53-WAFl/Cipl pathway may play a central role in induction of G, arrest following irradiation in human thyroid epithelial cells.