The relative radiosensitivity of TK6 and WI-L2-NS lymphoblastoid cells derived from a common source is primarily determined by their p53 mutational status

Abrogation of p53 function by HPV16 E6 gene delays apoptosis and enhances mutagenesis but does not alter radiosensitivity in TK6 human lymphoblast cells

“…The spontaneous and g-ray-induced mutation frequencies (MF) are shown for each of the ®ve cell lines. Total number of mutants, including both normal and slow growing ones, were used to calculate MF p53 expression and radiation response Y Yu et al responsible for the di erence in their radiosensitivities (Schwartz et al, 1995;Xia et al, 1995;Zhen et al, 1995). It was hypothesized that delayed apoptosis in the WTK1 may allow cells to divide at least once before apoptosis begins, thus e ectively doubling the number of cells which were seeded for the measurement of colony forming ability in the clonogenic survival assay for radiosensitivity.…”

“…The involvement of p53 in radiation-induced apoptosis has been demonstrated in a number of di erent cell types such as mouse thymocytes (Lowe et al, 1993). Although apoptosis has been demonstrated in cells expressing mutant p53, as in the case of WTK1 (Xia et al, 1995) and its parental line, WI-L2-NS (Schwartz et al, 1995;Zhen et al, 1995), it does not necessarily implicate a p53-independent mechanism since (1) certain mutant proteins may either adopt predominantly a wild type conformation or retain some p53 functions (Williams et al, 1995;Carrier et al, 1996), and (2) most p53 mutations are in either DNA-binding or transactivation regions and therefore will result in the loss of p53 transactivation potential. p53-dependent apoptosis, however, may occur in the absence of transcriptional activation of p53-e ector genes (Gottlieb et al, 1996), indicating the direct involvement of the p53 protein in the process.…”

Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53

“…For example, ionizing radiation and DNAdamaging agents have been shown to induce earlier apoptosis in human lymphoblastoid TK6 cells harboring wild-type p53 than in WTK-1 cells carrying mutant p53 (11)(12)(13)(14)(15). However, WTK-1 cells were about 20 times more sensitive to mutagenesis induced by 1.5-Gy x-rays and also showed a 10-fold higher spontaneous mutation rate at the autosomal heterozygous TK1 locus (16).…”

“…WTK-1 cells contain a T-to-C transition in exon 7 of the p53 gene, resulting in a substitution of Ile for Met at codon 237 (11)(12)(13)(14)(15). NO Y was delivered into stirred cell suspensions by diffusion through Silastic tubing at a constant rate and at levels similar to those estimated to occur in vivo in inflamed tissues (23).…”

Late G1 accumulation after 2 Gy of γ-irradiation is related to endogenous Raf-1 protein expression and intrinsic radiosensitivity in human cells

“…In some studies, expression of dominant oncogenes has been related to the duration of the G/M block and the degree of radiosensitivity as measured by clonogenic assay after radiation exposure (McKenna et al, 1991;Su and Little, 1993;Jung and Dritschilo, 1994;Warenius et al, 1996a). In other cases, modulation of the radiation-induced G1/S block (Fan et al, 1994;McIlwrath et al, 1994;Unger et al, 1994;Kawashima et al, 1995;Siles et al, 1996) or the induction of apoptosis (Lotem and Sachs, 1993;Lowe et al, 1994;Zhen et al, 1995) have been observed to correlate with differences in intrinsic cellular radiosensitivity. The molecular mechanism of post-irradiation G1 delay is understood to require, at least in part, p53 functionality (Kastan et al, 1991;Lee and Bernstein, 1993) and to act through transcriptional activation of the cyclin-dependent kinase inhibitor p21 WAFI/CIPI (Bae et al, 1995).…”