Komarova E A, Christov K, Faerman A I, Gudkov A V
Department of Molecular Genetics, University of Illinois at Chicago, 60607, USA.
Oncogene. 2000 Aug 3;19(33):3791-8. doi: 10.1038/sj.onc.1203717.
Mammalian tissues differ dramatically in their sensitivity to genotoxic stress, although the mechanisms determining these differences remain largely unknown. To analyse the role of p53 and p21 in determination of tissue specificity to DNA damage in vivo, we compared the effects of gamma radiation on DNA synthesis on whole-body sections of wild type, p53-deficient and p21-deficient mice. A dramatic reduction in 14C-thymidine incorporation after gamma irradiation was observed in the majority of rapidly proliferating tissues of wild type and p21-/- but not in p53-/- mice, confirming the key role of p53 in determination of tissue response to genotoxic stress in vivo and suggesting that p53-mediated inhibition of DNA synthesis does not depend on p21. Rapid radiation induced p53-dependent apoptosis was mapped to the areas of high levels of p53 mRNA in radiation sensitive tissues analysed (white pulp in the spleen and bases of crypts in small intestine), indicating that p53 regulation at the mRNA level is a determinant of cellular sensitivity to genotoxic stress. High p53 mRNA expression is inherited as a recessive trait in cell-cell hybrids suggesting the involvement of a negative control mechanism in the regulation of p53 gene expression.
哺乳动物组织对基因毒性应激的敏感性差异极大，尽管决定这些差异的机制在很大程度上仍不清楚。为了分析p53和p21在体内确定组织对DNA损伤的特异性中的作用，我们比较了γ辐射对野生型、p53缺陷型和p21缺陷型小鼠全身切片中DNA合成的影响。在野生型和p21 - / - 的大多数快速增殖组织中，γ照射后观察到14C - 胸苷掺入显著减少，但在p53 - / - 小鼠中未观察到，这证实了p53在体内确定组织对基因毒性应激反应中的关键作用，并表明p53介导的DNA合成抑制不依赖于p21。快速辐射诱导的p53依赖性凋亡定位于所分析的辐射敏感组织中p53 mRNA高水平的区域（脾脏中的白髓和小肠隐窝底部），表明mRNA水平的p53调节是细胞对基因毒性应激敏感性的决定因素。高p53 mRNA表达在细胞 - 细胞杂交体中作为隐性性状遗传，这表明负调控机制参与p53基因表达的调节。
