Comparison of endogenous TP53 genomic status with clonogenicity and different modes of cell death after X irradiation.
Although extensive data indicate that the tumor suppressor TP53 modifies the radiation responses of human and rodent cells, the exact relationship between TP53 and radiation responsiveness remains controversial. To elucidate the relevance of endogenous TP53 genomic status to radiosensitivity in a cell-type-independent manner, different cells of 10 human tumor cell lines with different tissues of origin were examined for TP53 status. The TP53 status was compared with radiation-related cell survival parameters (D(q), D(0), SF2) and with the mode of cell death. Different modes of cell death were examined by measuring radiation-induced micronucleation, apoptosis and abnormal cells. Alterations of the TP53 gene were detected in eight cell lines. No splicing mutation was found. Five cell lines showed codon 68 polymorphism. Codon 72 alterations were found in four cell lines. "Hot spot" alterations were detected in only two of 10 cell lines. Although the cells differed widely in survival parameters (D(q), D(0), SF2) and modes of cell death (micronucleation/apoptosis/abnormal cells) after irradiation, significant cell-type-independent correlations were obtained between the multiple cell death parameter micronucleation/apoptosis/abnormal cells and SF2 (P < 0.001) and D(q) (P = 0.003). Moreover, cells with a wild-type TP53 gene were more resistant to X rays than cells with a mutated TP53 gene or cells that were TP53-deficient. The alterations within exons 5-10 of the TP53 correlated with a enhanced radiosensitivity. For the first time, we demonstrated a correlation between endogenous genetic alterations within exons 5-10 of TP53 and radiation-related cell survival and cell death. This indicates a new molecular relevance of TP53 status to intrinsic cellular radiosensitivity.
Lu-Hesselmann
Juxian
J
Institute of Radiobiology, Federal Armed Forces Medical Academy of Germany, Munich, Neuherbergstr. 11, 80937 Munich, Germany.
Abend
Michael
M
van Beuningen
Dirk
D
D017209:Apoptosis / Q000528:radiation effects*; D045744:Cell Line, Tumor / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D003114:Colony-Forming Units Assay / Q000379:methods*; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D015162:Micronucleus Tests; D009154:Mutation / Q000528:radiation effects; D009369:Neoplasms / Q000378:metabolism*; D009928:Organ Specificity; D011829:Radiation Dosage; D011836:Radiation Tolerance; D017422:Sequence Analysis, DNA / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53