Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of β-catenin depending on the status of cellular p53
Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of β-catenin depending on the status of cellular p53
复制标题
DOI：
10.1099/vir.0.82836-0
复制
发表时间：
2007-08-01
影响因子：
3.8
通讯作者：
Jang, Kyung Lib
中科院分区：
文献类型：
--
作者：
Jung, Jin Kyu;Kwun, Hyun Jin;Jang, Kyung Lib
β-catenin的异常积聚被认为是肝细胞癌发生的强大驱动力，然而，β-catenin在肝细胞癌发生过程中的积聚机制尚不清楚。在这里，它被证明，肝炎B病毒X蛋白（HBx）差异调节β-连环蛋白的水平，通过两个泛素依赖性蛋白酶体途径依赖于p53的状态。在p53存在的情况下，HBx通过激活p53-Siah-1蛋白酶体途径下调β-连环蛋白。为此，HBx通过激活p53在转录水平上调Siah-1的表达。然而，在p53不存在的情况下，HBx通过抑制糖原合成酶激酶-3 β依赖性途径稳定β-连环蛋白。有趣的是，具有Pro-101到Ser取代的HBx变体不能激活p53，因此可以稳定β-连环蛋白，而不管p53状态如何。基于这些发现，提出了HBx调控β-连环蛋白的模型，其中HBx的两种相反活性之间的平衡决定了β-连环蛋白的总体表达水平。HBx对β-连环蛋白的差异调节取决于宿主（p53状态）和病毒因素（HBx序列变异），这不仅有助于解释积累β-连环蛋白的癌症也表现出高频率的p53突变的观察结果，而且有助于理解关于HBx在肝细胞癌发生过程中作用的相互矛盾的报道。
Abnormal accumulation of beta-catenin is considered to be a strong driving force in hepatocellular carcinogenesis; however, the mechanism of beta-catenin accumulation in turnours is unclear. Here, it was demonstrated that hepatitis B virus X protein (HBx) differentially regulates the level of beta-catenin through two ubiquitin-dependent proteasome pathways depending on p53 status. In the presence of p53, HBx downregulated beta-catenin through the activation of a p53-Siah-1 proteasome pathway. For this purpose, HBx upregulated Siah-1 expression at the transcriptional level via activation of p53. In the absence of p53, however, HBx stabilized beta-catenin through the inhibition of a glycogen synthase kinase-3 beta-dependent pathway. Interestingly, HBx variants with a Pro-101 to Ser substitution were unable to activate p53 and thus could stabilize beta-catenin irrespective of p53 status. Based on these findings, a model of beta-catenin regulation by HBx is proposed whereby the balance between the two opposite activities of HBx determines the overall expression level of beta-catenin. Differential regulation of beta-catenin by HBx depending on host (p53 status) and viral factors (HBx sequence variation) helps not only to explain the observation that cancers accumulating beta-catenin also exhibit a high frequency of p53 mutations but also to understand the contradictory reports on the roles of HBx during hepatocellular carcinogenesis.