Physical and functional interactions between Daxx and STAT3
Physical and functional interactions between Daxx and STAT3
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DOI：
10.1038/sj.onc.1209235
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发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Matsuda, T
中科院分区：
文献类型：
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作者：
Muromoto, R;Nakao, K;Matsuda, T
信号转导和转录激活因子3(STAT3)在白介素6(IL-6)家族的细胞内信号通路中起着关键作用，表现出包括细胞增殖和分化在内的一系列不同的细胞反应。IL-6/STAT3信号转导异常参与了自身免疫性疾病和肿瘤等多种疾病的发病过程。I型干扰素可诱导促凋亡基因的表达，目前已用于多种肿瘤的临床治疗。在本研究中，我们发现I型干扰素抑制IL-6/STAT3介导的转录和基因表达。此外，I型干扰素诱导蛋白Daxx也抑制STAT3介导的转录激活，而过表达Daxx则抑制IL-6/STAT3介导的基因表达。重要的是，小干扰RNA介导的Daxx表达下调增强了IL-6/白血病抑制因子(LIF)诱导的STAT3依赖的转录。免疫共沉淀研究表明Daxx和STAT3在瞬时转染的293T细胞中存在物理相互作用。我们进一步发现Daxx和STAT3共定位于细胞核中。这些结果表明，Daxx可能是I型干扰素介导的抑制IL-6/STAT3信号通路的转录调节因子。
Signal transducer and activator of transcription 3 (STAT3) play key roles in the intracellular signaling pathways of the interleukin (IL)-6 family of cytokines, which exhibit a diverse set of cellular responses, including cell proliferation and differentiation. Dysregulated IL-6/STAT3 signaling is involved in the pathogenesis of several diseases, for example autoimmune diseases and tumors. Type I interferon (IFN) induces the expression of proapoptotic genes and has been used in the clinical treatment of several tumors. In the present study, we found that type I IFN suppressed IL-6/STAT3-mediated transcription and gene expression. Furthermore, a type I IFN-induced protein, Daxx, also suppressed STAT3-mediated transcriptional activation, while overexpression of Daxx inhibited IL-6/STAT3-mediated gene expression. Importantly, small-interfering RNA-mediated reduction of Daxx expression enhanced IL-6/leukemia inhibitory factor (LIF)-induced STAT3-dependent transcription. Co-immunoprecipitation studies revealed a physical interaction between Daxx and STAT3 in transiently transfected 293T cells. We further found that Daxx and STAT3 were co-localized in the nucleus. These results indicate that Daxx may serve as a transcriptional regulator of type I IFN-mediated suppression of the IL-6/STAT3 signaling pathway.