Blocking of G1/S transition and cell death in the regenerating liver of Hepatitis B virus X protein transgenic mice
Blocking of G1/S transition and cell death in the regenerating liver of Hepatitis B virus X protein transgenic mice
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DOI：
10.1016/j.bbrc.2005.12.089
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发表时间：
2006-02-17
影响因子：
3.1
通讯作者：
Tsai, TF
中科院分区：
文献类型：
--
作者：
Wu, BK;Li, CC;Tsai, TF
乙型肝炎病毒 X (HBx) 蛋白与肝细胞癌 (HCC) 的致癌作用密切相关。然而，HBx 蛋白对细胞增殖和细胞死亡的影响存在争议。本研究调查了 HBx 蛋白油对两个独立的 HBx 转基因小鼠品系的肝再生的影响，这些小鼠在 14 至 16 个月大时患上 HCC。肝切除后的 HBx 转基因小鼠中发现死亡率高、肝脏质量恢复较低和肝再生受损。肝切除后检测到的丙氨酸氨基转移酶和甲胎蛋白水平在HBx转基因肝脏中显着增加，表明它们在再生过程中更容易受到损伤。 HBx转基因肝脏中立即早期基因的长时间激活表明HBx蛋白通过促进静止肝细胞从G0期向G1期的转变产生强大的作用。然而，检测到 DNA 合成和有丝分裂受损，以及 G 1、S 和 G2/M 标记的激活受到抑制。这些结果表明，HBx 蛋白对肝细胞产生强烈的生长抑制作用，并导致细胞周期进程失衡，导致细胞异常死亡。这还伴随着 HBx 转基因肝脏中严重的脂肪积累和糖原储存受损。总之，这项研究提供了第一个生理学证据，证明 HBx 蛋白阻断肝细胞细胞周期进程的 G1/S 转变，并导致 HBx 转基因小鼠再生肝脏的肝功能衰竭和细胞死亡。 (c) 2005 Elsevier Inc. 保留所有权利。
The Hepatitis B Virus X (HBx) protein has been strongly implicated in the carcinogenesis of hepatocellular carcinoma (HCC). However, effects of the HBx protein on cell proliferation and cell death are controversial. This study investigates the effects of the HBx protein oil liver regeneration in two independent lines of HBx transgenic mice, which developed HCC at around 14 to 16 months of age. High mortality, lower liver mass restoration, and impaired liver regeneration were found in the HBx transgenic mice post-hepatectomy. The levels of alanine aminotransferase and alpha-fetoprotein detected post-hepatectomy increased significantly in the HBx transgenic livers, indicating that they were more susceptible to damage during the regenerative process. Prolonged activation of the immediate-early genes in the HBx transgenic livers Suggested that the HBx protein creates a strong effect by promoting the transition of the quiescent hepatocytes from G0 to G1 phase. However, impaired DNA synthesis and mitosis, as well as inhibited activation of G 1, S, and G2/M markers, were detected. These results indicated that HBx protein exerted strong growth arrest on hepatocytes and imbalanced cell-cycle progression resulting in the abnormal cell death; this was accompanied by severe fat accumulation and impaired glycogen storage in the HBx transgenic livers. In conclusion, this study provides the first physiological evidence that HBx protein blocks G1/S transition of the hepatocyte cell-cycle progression and causes both a failure of liver functionality and cell death in the regenerating liver of the HBx transgenic mice. (c) 2005 Elsevier Inc. All rights reserved.