COMBINATORIAL ASSOCIATION AND ABUNDANCE OF COMPONENTS OF INTERFERON-STIMULATED GENE FACTOR-3 DICTATE THE SELECTIVITY OF INTERFERON RESPONSES
COMBINATORIAL ASSOCIATION AND ABUNDANCE OF COMPONENTS OF INTERFERON-STIMULATED GENE FACTOR-3 DICTATE THE SELECTIVITY OF INTERFERON RESPONSES
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DOI：
10.1073/pnas.92.12.5645
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发表时间：
1995-06-06
影响因子：
11.1
通讯作者：
LEVY, DE
中科院分区：
文献类型：
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作者：
BLUYSSEN, HAR;MUZAFFAR, R;LEVY, DE
含有干扰素刺激反应元件（ISRE）增强子的基因已被表征为主要对I型干扰素（IFN α/β）有转录应答。诱导是由于多聚体转录因子干扰素刺激基因因子3（ISGF 3）的激活，其被IFN α/β激活，但不被IFN γ激活。我们发现，在Vero细胞中，含有ISRE的基因被IFN γ和IFN α诱导。IFN γ应答依赖于ISRE，并且通过将细胞预先暴露于IFN α而增强，IFN α是一种增加ISGF 3组分丰度的处理，ISGF 3多肽的过表达表明IFN γ应答依赖于DNA结合蛋白ISGF 3 γ（p48）以及91-kDa蛋白STAT 91（Stat 1 α）。除了STAT 91和p48之外，对IFN α的转录应答还需要113-kDa蛋白STAT 113（Stat 2）。使用缺乏ISGF 3的每种组分的突变纤维肉瘤细胞来证实ISRE报告基因的IFN γ诱导需要p48和STAT 91，而不是STAT 113。含有p48和磷酸化STAT 91但缺乏STAT 113的复合物在体外结合ISRE。IFN γ诱导的这种复合物的活化，优先在高浓度的p48和STAT 91下形成，可以解释对IFN α和IFN γ的一些重叠应答。
Genes containing the interferon-stimulated response element (ISRE) enhancer have been characterized as transcriptionally responsive primarily to type I interferons (IFN alpha/beta), Induction is due to activation of a multimeric transcription factor, interferon-stimulated gene factor 3 (ISGF3), which is activated by IFN alpha/beta but not by IFN gamma. We found that ISRE-containing genes were induced by IFN gamma as well as by IFN alpha in Vero cells, The IFN gamma response was dependent on the ISRE and was accentuated by preexposure of cells to IFN alpha, a treatment that increases the abundance of ISGF3 components, Overexpression of ISGF3 polypeptides showed that the IFN gamma response depended on the DNA-binding protein ISGF3 gamma(p48) as well as on the 91-kDa protein STAT91 (Stat1 alpha). The transcriptional response to IFN alpha required the 113-kDa protein STAT113 (Stat2) in addition to STAT91 and p48. Mutant fibrosarcoma cells deficient in each component of ISGF3 were used to confirm that IFN gamma induction of an ISRE reporter required p48 and STAT91, but not STAT113. A complex containing p48 and phosphorylated STAT91 but lacking STAT113 bound the ISRE in vitro. IFN gamma-induced activation of this complex, preferentially formed at high concentrations of p48 and STAT91, mag explain some of the overlapping responses to IFN alpha and IFN gamma.