Leu Julia I-Ju, Murphy Maureen E, George Donna L
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Liver. 2013;2(1). doi: 10.4172/2167-0889.1000117.
The p53 protein is a critical stress-response mediator and signal coordinator in cellular metabolism and environmental exposure to deleterious agents. In human populations, the p53 gene contains a common single nucleotide polymorphism (SNP) affecting codon 72 that determines whether a proline (P72) or an arginine (R72) is present at this amino acid position of the polypeptide. Previous studies carried out using human populations, mouse models, and cell culture analyses have provided evidence that this amino acid difference can alter p53 functional activities, and potentially also can affect clinical presentation of disease. The clinical presentation associated with many forms of liver disease is variable, but few of the responsible underlying genetic factors or molecular pathways have been identified. The aim of the present study was to investigate whether the p53 codon 72 polymorphism influences the cellular response to hepatic stresses. A humanized p53 knock-in (Hupki) mouse model was used to address this issue. Mice expressing either the P72 or R72 normal variation of p53 were given an acute-, intermittent- or a chronic challenge, associated with exposure to lipopolysaccharide, D-galactosamine, or a high-fat diet. The results reveal that the livers of the P72 and R72 mice exhibit notable differences in inflammatory and apoptotic response to these distinct forms of stress. Interestingly the influence of this polymorphism on the response to stress is context dependent, with P72 showing increased response to liver toxins (lipopolysaccharide and D-galactosamine), but R72 showing increased response to metabolic stress (high fat diet). When taken together, these data point to the p53 codon 72 polymorphism as an important molecular mediator of events contributing to hepatic inflammation and metabolic homeostasis.
p53蛋白是细胞代谢以及暴露于有害因子环境下时关键的应激反应介质和信号协调因子。在人类群体中，p53基因包含一个影响密码子72的常见单核苷酸多态性（SNP），该多态性决定了多肽此氨基酸位置上是脯氨酸（P72）还是精氨酸（R72）。此前利用人类群体、小鼠模型和细胞培养分析开展的研究已提供证据表明，这种氨基酸差异可改变p53的功能活性，并且可能还会影响疾病的临床表现。与多种肝病相关的临床表现具有多样性，但几乎未鉴定出任何相关的潜在遗传因素或分子途径。本研究的目的是调查p53密码子72多态性是否会影响细胞对肝应激的反应。为此使用了一种人源化p53基因敲入（Hupki）小鼠模型。对表达p53正常P72或R72变体的小鼠进行急性、间歇性或慢性刺激，这些刺激与接触脂多糖、D-半乳糖胺或高脂饮食有关。结果显示，P72和R72小鼠的肝脏在对这些不同形式应激的炎症和凋亡反应方面表现出显著差异。有趣的是，这种多态性对应激反应的影响取决于具体情况，P72对肝毒素（脂多糖和D-半乳糖胺）的反应增强，而R72对代谢应激（高脂饮食）的反应增强。综合来看，这些数据表明p53密码子72多态性是导致肝脏炎症和代谢稳态相关事件的重要分子介质。
