Modulation of interferon (IFN)-inducible gene expression by retinoic acid - Up-regulation of STAT1 protein in IFN-unresponsive cells
Modulation of interferon (IFN)-inducible gene expression by retinoic acid - Up-regulation of STAT1 protein in IFN-unresponsive cells
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DOI：
10.1074/jbc.271.18.10508
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发表时间：
1996-05-03
影响因子：
4.8
通讯作者：
Kalvakolanu, DV
中科院分区：
文献类型：
--
作者：
Kolla, V;Lindner, DJ;Kalvakolanu, DV
干扰素（IFN）和类维生素a不能抑制许多乳腺肿瘤细胞系的生长，然而，在药理学上可达到的剂量下，这两种生物反应调节剂联合使用可显著抑制细胞生长。我们在MCF-7中研究了这种增强的分子基础，MCF-7是一种抵抗ifn - β生长抑制的乳腺肿瘤细胞系。用视黄酸（RA）预处理细胞16小时后再用ifn - β，可诱导细胞毒性作用，而非相反。RA的持续存在是不必要的，尽管它增加了细胞死亡的程度。进一步的分析表明，ifn - β不能激活ifn刺激的基因转录。然而，ifn - β在ra预处理的细胞中强烈上调基因表达。ifn - β和ifn - γ诱导的基因表达均通过调节转录因子ifn刺激的基因因子-3和GAF与各自同源调控元件的结合而增强。在类风湿关节炎治疗之前，在这些细胞中检测不到STAT1：类风湿关节炎增加了这种关键调节因子的水平，从而恢复了IFN反应。因此，BA中STAT1的增加可能是IFN和RA协同抗肿瘤作用的早期步骤。
Interferons (IFN) and retinoids failed to inhibit the growth of a number of breast tumor cell lines, However, a combination of these two biological response modifiers significantly suppressed the cell growth at pharmacologically achievable doses. The molecular basis for such enhancement was investigated in MCF-7, a breast tumor cell line resistant to growth inhibition by IFN-beta. Pretrentment of cells with retinoic acid (RA) for 16 h followed by IFN-beta, but not the converse, induced cytotoxic effects in the cells. Continuous presence of RA was not necessary, although it enhanced the degree of cell death when present. Further analyses revealed that IFN-beta failed to activate IFN-stimulated gene transcription. However, IFN-beta strongly up-regulated the gene expression in RA-pretreated cells. Both IFN-beta- and IFN-gamma-inducible gene expression were enhanced via a modulation of the transcriptional factor IFN-stimulated gene factors-3 and GAF binding to respective cognate regulatory elements. STAT1 was undetectable in these cells prior to RA treatment: RA increased the levels of this crucial regulator, thereby restoring IFN responses. Thus, BA augmentation of STAT1 may be an early step in the cooperative anti-tumor effects of IFN and RA.