The promyelocytic leukemia protein functions as a negative regulator of IFN-γ signaling
The promyelocytic leukemia protein functions as a negative regulator of IFN-γ signaling
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DOI：
10.1073/pnas.0604800103
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发表时间：
2006-12-05
影响因子：
11.1
通讯作者：
Benveniste, Etty N.
中科院分区：
文献类型：
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作者：
Choi, Youn-Hee;Bernardi, Rosa;Benveniste, Etty N.
IFN-γ是一种免疫调节细胞因子，并使用STAT-1 α转录因子介导基因表达。早幼粒细胞白血病（PML）蛋白作为激活子或抑制子调节转录，具体取决于所研究的基因。在此，我们使用PML野生型（Pml（+/+））和缺陷型（Pml（-/-））小鼠胚胎成纤维细胞（MEF）检测PML对IFN-γ信号传导的影响。与Pml（+/+）细胞相比，Pml（-/-）MEF表现出增强的IFN-γ诱导的STAT-1 α转录活性。此外，在Pml（-/-）MEF中重构PML将STAT-1 α转录活性降低至与Pml（+/+）MEF相当的水平。与Pml（+/+）MEF相比，Pml（-/-）MEF中许多内源性IFN-γ调节基因表达上调。与Pml（+/+）细胞相比，IFN-γ介导的STAT-1 α DNA结合活性在Pml（-/-）细胞中增强。最后，IFN-γ增强了细胞核中PML-STAT-1 α复合物的形成。这些数据表明PML通过抑制STAT-1 α DNA结合和转录活性在IFN-γ信号通路中具有新的功能。
IFN-gamma is an immunomodulatory cytokine and uses the STAT-1 alpha transcription factor to mediate gene expression. The promyelocytic leukemia (PML) protein regulates transcription as an activator or repressor, depending on the gene under investigation. Herein, we examined the influence of PML on IFN-gamma signaling, using PML wild-type (Pml(+/+)) and deficient (Pml(-/-)) mouse embryonic fibroblasts (MEF). Pml(-/-) MEF exhibit enhanced IFN-gamma-induced STAT-1 alpha transcriptional activity compared with Pml(+/+) cells. Moreover, reconstitution of PML in Pml(-/-) MEF reduced STAT-1 alpha transcriptional activity to levels comparable to Pml(+/+) MEF. Numerous endogenous IFN-gamma-regulated genes were up-regulated in Pml(-/-) MEF compared with Pml(+/+) MEF. IFN-gamma-mediated STAT-1 alpha DNA-binding activity was enhanced in Pml(-/-) cells compared with Pml(+/+) cells. Lastly, IFN-gamma enhanced the formation of a PML-STAT-1 alpha complex in the nucleus. These data suggest a novel function for PML in the IFN-gamma signaling pathway by inhibiting STAT-1 alpha DNA binding and transcriptional activity.