TRANSACTIVATION BY HEPATITIS-B VIRUS X-PROTEIN IS PROMISCUOUS AND DEPENDENT ON MITOGEN-ACTIVATED CELLULAR SERINE THREONINE KINASES
TRANSACTIVATION BY HEPATITIS-B VIRUS X-PROTEIN IS PROMISCUOUS AND DEPENDENT ON MITOGEN-ACTIVATED CELLULAR SERINE THREONINE KINASES
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DOI：
10.1073/pnas.90.17.8078
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发表时间：
1993-09-01
影响因子：
11.1
通讯作者：
RUTTER, WJ
中科院分区：
文献类型：
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作者：
CROSS, JC;WEN, P;RUTTER, WJ
B型肝炎病毒X蛋白（HBV-X）是一种转录激活因子，但其作用机制尚不清楚。我们已经分析了HBV-X的反式激活在几种细胞类型中使用13个无关的病毒和细胞的启动子，发现反式激活是或多或少的明显在大多数细胞类型，是混杂的和无关的特定序列基序内的目标启动子。一般来说，HBV-X似乎作用于增强子元件，因为HBV-X对最小启动子没有影响，而HBV-X在插入AP-1微型增强子后能够反式激活。几条证据排除了HBV-X直接与AP-1增强子或其结合蛋白相互作用的可能性，并表明HBV-X的近端靶点位于转录复合物的外周。这一假设得到以下观察结果的支持：抑制调节AP-1活性的丝氨酸/苏氨酸激酶（佛波醇酯下调或星形孢菌素抑制蛋白激酶C和Raf-1的显性负突变体），阻断HBV-X反式激活的能力，而不影响基础启动子活性。此外，AP-1依赖性启动子的基础转录通过蛋白激酶C和Raf-1的过表达而增加，但HBV-X不能进一步刺激，表明这些激酶在HBV-X之后起作用。这些数据表明，HBV-X的反式激活是细胞丝氨酸/苏氨酸激酶（包括蛋白激酶C和Raf-1）激活的间接结果。这种作用模式意味着HBV-X可能影响其他细胞过程，除了转录，这些激酶调节。
The X protein of hepatitis B virus (HBV-X) can act as a transactivator of transcription but its mechanism of action remains obscure. We have analyzed HBV-X transactivation in several cell types using 13 unrelated viral and cellular promoters and found that transactivation is more or less apparent in most cell types and is promiscuous and unrelated to specific sequence motifs within the target promoters. In general, though, HBV-X appears to act on enhancer elements since HBV-X had no effect on a minimal promoter, whereas HBV-X was able to transactivate after insertion of an AP-1 minienhancer. Several lines of evidence exclude the possibility that HBV-X interacts directly with the AP-1 enhancer or its binding proteins and suggest that the proximal target of HBV-X is peripheral to the transcription complex. This hypothesis is supported by the observation that inhibition of serine/threonine kinases, which regulate AP-1 activity (phorbol ester down-regulation or staurosporine inhibition of protein kinase C and a dominant negative mutant of Raf-1), blocked the ability of HBV-X to transactivate without affecting basal promoter activity. Furthermore, basal transcription from the AP-1-dependent promoter was increased by overexpression of protein kinase C and Raf-1 but HBV-X was unable to further stimulate, indicating that these kinases act subsequently to HBV-X. These data suggest that transactivation by HBV-X is an indirect result of the activation of cellular serine/threonine kinases including protein kinase C and Raf-1. This mode of action implies that HBV-X may affect other cellular processes, besides transcription, that are regulated by these kinases.