Background & Aims

A coordinated stress and regenerative response is important after hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the checkpoint kinase 2/transformation-related protein 53 (p53)/cyclin-dependent kinase inhibitor 1A (p21) pathway in a murine model of metabolic liver injury.

Methods

Nitisinone was reduced or withdrawn in Fah^-/- mice lacking Chk2, p53, or p21, and survival, tumor development, liver injury, and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas antibody Jo2.

Results

In a model of metabolic liver injury, loss of p53, but not Chk2, impairs the oxidative stress response and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell-cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, showing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the distinct phenotypes associated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on proliferation and the anti-oxidative stress response.

Conclusions

Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage-response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, is related to the level at which the cascade is interrupted. Accession numbers of repository for expression microarray data: GSE156983, GSE156263, GSE156852, and GSE156252.

中文翻译：

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p21 的 p53 非依赖性诱导无法控制小鼠肝损伤模型中的再生和肝癌发生

背景与目标

在肝细胞损伤后，协调的压力和再生反应很重要。在这里，我们研究了代谢性肝损伤小鼠模型中检查点激酶 2/转化相关蛋白 53 (p53)/细胞周期蛋白依赖性激酶抑制剂 1A (p21) 通路的单个成分的遗传消除导致的表型。

方法

在缺乏Chk2、p53或p21的Fah ^-/-小鼠中减少或停用尼替西农，并分析了存活、肿瘤发展、肝损伤和再生。进行部分肝切除术，并用 Fas 抗体 Jo2 攻击小鼠。

结果

在代谢性肝损伤模型中，p53而不是Chk2的缺失会损害氧化应激反应并加重肝损伤，这表明 p53 对肝细胞具有直接的依赖性保护作用。慢性肝损伤期间的细胞周期控制主要取决于 p53 及其下游效应子 p21 的存在。在p53- 肝细胞缺陷，尽管 p21 强烈诱导，但仍会发生不受控制的增殖，表明 p21 和 p53 之间存在复杂的相互依赖性。在没有 p53 的情况下增加的再生潜力不能完全补偿多余的损伤，也不足以促进生存。尽管与 DNA 损伤反应的单个成分丢失相关的不同表型，基因表达模式主要由肝损伤的严重程度决定，但反映了 p53 对增殖和抗氧化应激反应的不同影响。

结论

特征性表型是由于肝损伤模型中 DNA 损伤反应级联的单个成分的遗传消除所致。可以补偿基因功能损失或影响损伤和增殖的程度与级联中断的水平有关。表达微阵列数据存储库的登录号：GSE156983、GSE156263、GSE156852 和 GSE156252。