p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine.
p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine.
复制标题
DOI：
10.3390/ijms19030921
复制
发表时间：
2018-03-20
影响因子：
5.6
通讯作者：
Prokesch A
中科院分区：
文献类型：
--
作者：
Krstic J;Galhuber M;Schulz TJ;Schupp M;Prokesch A
与生活方式相关的疾病，如代谢综合征，已成为肝脏病理发展的主要危险因素，这些疾病可从肝脏脂肪变性、肝脏胰岛素抵抗、脂肪性肝炎、纤维化和肝硬变发展到最严重的肝细胞癌(HCC)。虽然在现代社会，肝脏病理的患病率正在稳步上升，但目前除了化疗干预外，还没有批准的药物治疗晚期肝癌。因此，迫切需要识别和研究能够产生新的治疗途径的致病分子途径。转录因子P53被公认为是一种肿瘤抑制因子，最近被描述为生理和病理环境中的中心代谢参与者。鉴于肝脏是一个动态的组织，直接暴露于摄入的营养物质，肝脏P53通过整合细胞应激反应、代谢和细胞周期调节而成为肝脏动态平衡和功能障碍的重要调节因子。本文回顾了P53活性对肝脏疾病不同阶段的直接影响的临床数据和动物研究的基本证据。根据目前的文献显示，激活P53信号可以减轻或加剧肝脏疾病，我们在这里讨论了这样的假设：虽然过度激活或功能丧失可以导致疾病，但在生理范围内适度诱导肝脏P53可能有助于预防和治疗肝脏病理。因此，导致适度和暂时的P53激活的刺激可以通过从肝脏脂肪变性到肝细胞癌的级联反应的几个入口点提供新的治疗方法。
Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC.
登录
查看更多内容
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
11.2
作者：
Chen, Ya-Wen;Klimstra, David S.;Lewis, Brian C.
通讯作者：
Lewis, Brian C.
影响因子：
6.6
作者：
Aylon Y;Oren M
通讯作者：
Oren M
影响因子：
4.3
作者：
Cervello, Melchiorre;Bachvarov, Dimcho;Montalto, Giuseppe
通讯作者：
Montalto, Giuseppe
影响因子：
25.7
作者：
Castro, Rui E.;Ferreira, Duarte M. S.;Rodrigues, Cecilia M. P.
通讯作者：
Rodrigues, Cecilia M. P.