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首页> 外文期刊>Journal of Molecular Biology >Induction of activator protein 1 (AP-1) in macrophages by human immunodeficiency virus type-1 NEF is a cell-type-specific response that requires both hck and MAPK signaling events.
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Induction of activator protein 1 (AP-1) in macrophages by human immunodeficiency virus type-1 NEF is a cell-type-specific response that requires both hck and MAPK signaling events.

机译：人类免疫缺陷病毒1型NEF在巨噬细胞中诱导活化蛋白1（AP-1）是一种细胞类型特异性应答，需要hck和MAPK信号转导事件。

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Human immunodeficiency virus type 1 (HIV-1) Nef is important for viral infectivity and pathogenicity. HIV-1 infection is associated with inappropriate activation and defects in the function of monocytes/macrophages. We have studied the effects of HIV-1 Nef in the murine (RAW264.7) and human (THP-1) monocyte-macrophage cell lines. Investigation of the activator protein-1 (AP-1) transcription factor showed that Nef expression induced both its DNA binding and transcriptional activities. Increased AP-1 DNA binding activity in RAW264.7 cells was associated with raised levels of c-Fos expression and induction of mRNA for the AP-1 responsive tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. Mutagenesis and kinase inhibition studies were employed to determine signaling pathways used by Nef to induce AP-1. Data from these studies indicated that induction of AP-1 by Nef is likely to be mediated through the MAPK (ERK1 and 2) signaling pathway and requires the proline-rich PxxP motif of Nef, suggesting the involvement of upstream protein kinases belonging to the Src family. Effects of Nef on AP-1 induction were cell lineage-specific, being stimulatory in macrophages, inhibitory in T cells and without effect in HeLa cells. These latter two observations led us to test the possibility that cell-specific interactions of Nef with Src family proteins may modulate AP-1 activity. To this end we demonstrated that a dominant-negative Hck mutant caused inhibition of Nef-mediated AP-1 DNA binding activity in RAW cells. In conclusion, induction of AP-1 by Nef is a specific feature of human and murine macrophage cell lines that requires signal transduction events involving Hck and MAPKs. Copyright 1999 Academic Press.
机译：人类1型免疫缺陷病毒（HIV-1）Nef对病毒的感染性和致病性很重要。 HIV-1感染与不适当的激活和单核细胞/巨噬细胞功能缺陷有关。我们已经研究了HIV-1 Nef在鼠（RAW264.7）和人（THP-1）单核巨噬细胞细胞系中的作用。对活化蛋白1（AP-1）转录因子的研究表明，Nef表达诱导了其DNA结合和转录活性。 RAW264.7细胞中增加的AP-1 DNA结合活性与c-Fos表达水平的提高和金属蛋白酶1（TIMP-1）基因的AP-1反应性组织抑制剂的mRNA诱导有关。诱变和激酶抑制研究被用于确定Nef用来诱导AP-1的信号通路。这些研究的数据表明，Nef对AP-1的诱导可能是通过MAPK（ERK1和2）信号传导途径介导的，并且需要Nef富含脯氨酸的PxxP基序，这暗示了属于Src的上游蛋白激酶的参与家庭。 Nef对AP-1诱导的作用是细胞谱系特异性的，对巨噬细胞有刺激作用，对T细胞有抑制作用，对HeLa细胞无作用。后两个观察结果使我们测试了Nef与Src家族蛋白的细胞特异性相互作用可能调节AP-1活性的可能性。为此，我们证明了显性阴性的Hck突变体可抑制RAW细胞中Nef介导的AP-1 DNA结合活性。总之，Nef诱导AP-1是人和鼠巨噬细胞系的一个特定特征，需要涉及Hck和MAPK的信号转导事件。版权所有1999，学术出版社。

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