THE HEPATITIS-B VIRUS HBX PROTEIN IS A DUAL-SPECIFICITY CYTOPLASMIC ACTIVATOR OF RAS AND NUCLEAR ACTIVATOR OF TRANSCRIPTION FACTORS
THE HEPATITIS-B VIRUS HBX PROTEIN IS A DUAL-SPECIFICITY CYTOPLASMIC ACTIVATOR OF RAS AND NUCLEAR ACTIVATOR OF TRANSCRIPTION FACTORS
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DOI：
10.1002/j.1460-2075.1995.tb00156.x
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发表时间：
1995-10-02
期刊：
影响因子：
11.4
通讯作者：
SCHNEIDER, RJ
中科院分区：
文献类型：
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作者：
DORIA, M;KLEIN, N;SCHNEIDER, RJ
乙型肝炎病毒 (HBV) 的 HBx 蛋白是感染所需的转录激活剂，可能在 HBV 相关肝癌发生中发挥重要作用。最近，我们和其他人表明，HBx 刺激 Ras-Raf-MAP 激酶级联，从而导致细胞增殖增强以及转录因子 AP-1 和 NF-kappa B 的激活，其他研究表明 HBx 可以通过直接与转录机器的核组件相互作用来激活转录，因此我们检查了 HBx 不同报道活性的基础，在这里，我们表明 HBx 是一种复杂的蛋白质，在不同的细胞内位置表现出独立的活性，首先使用扫描共聚焦激光免疫显微镜和遗传学研究对 HBx 蛋白进行了研究，我们的工作已经确定，在培养细胞中表达的 HBx 在细胞质和细胞核中均真实存在，HBx 与任何细胞内结构没有很强的相关性，但在细胞表面附近观察到一些优先积累，接下来，构建了包含功能性或突变核定位序列的 HBx 变体，我们表明，当 HBx 被设计为专门重新定位到细胞核时，它不再激活Ras-Raf-MAP 激酶级联反应，也不激活转录因子 AP-1 和 NF-kappa B。令人惊讶的是，核 HBx 完全保留了刺激 HBV 增强子 I 的能力，该增强子 I 的激活独立于 Ras 和蛋白激酶 C 途径，因此 HBx 蛋白刺激细胞质中的信号转导途径并反式激活细胞核中的转录元件。此外，SV40 T 抗原显示可诱导 HBx 蛋白的核隔离并阻断它激活 NF-kappa B，表明 HBx 受到改变其细胞内分布的蛋白质的调节。 HBx 蛋白在病毒感染和可能的癌症中的相互冲突的功能可能涉及其在细胞中差异分布的调节。
The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B, Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery, Therefore we examined the basis for the different reported activities of HBx, Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations, The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies, Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus, HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface, Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence, We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways, Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus, Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.