Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN)
Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN)
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DOI：
10.1073/pnas.0807975106
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Su, Zao-Zhong;Lee, Seok-Geun;Fisher, Paul B.
我们描述了一种新型碱性亮氨酸拉链，含有 I 型 IFN 诱导的早期反应基因 SARI（AP-1 抑制因子，受 IFN 调节）。在多个谱系特异性正常细胞中检测到稳态 SARI mRNA 表达，但在转化/致瘤细胞中未检测到。在正常细胞和癌细胞中，用 1 U/ml IFN-β 处理成纤维细胞 IFN (IFN-β) 2 小时后，SARI 表达被诱导。 SARI 的反义抑制可保护 HeLa 细胞免受 IFN-β 介导的生长抑制。作为推论，SARI 的过度表达会抑制癌细胞的生长并诱导细胞凋亡，但不会影响正常细胞。 SARI 通过其亮氨酸拉链与 c-Jun 相互作用，从而抑制激活蛋白 (AP-1) 复合物的 DNA 结合，从而抑制 AP-1 依赖性基因表达。依赖 AP-1 活性获得增殖优势的转化细胞表现出对 SARI 介导的生长抑制的敏感性增加。这些发现揭示了 IFN 诱导的抗肿瘤生长抑制的新模式，并提示 SARI 的潜在基因治疗应用。
We describe a novel basic leucine zipper containing type I IFN-inducible early response gene SARI (Suppressor of AP-1, Regulated by IFN). Steady-state SARI mRNA expression was detected in multiple lineage-specific normal cells, but not in their transformed/tumorigenic counterparts. In normal and cancer cells, SARI expression was induced 2 h after fibroblast IFN (IFN-beta) treatment with 1 U/ml of IFN-beta. Antisense inhibition of SARI protected HeLa cells from IFN-beta-mediated growth inhibition. As a corollary, overexpression of SARI inhibited growth and induced apoptosis in cancer cells, but not in normal cells. SARI interacted with c-Jun via its leucine zipper, resulting in inhibition of DNA binding of activator protein (AP-1) complex and consequently AP-1-dependent gene expression. Transformed cells relying on AP-1 activity for proliferative advantage demonstrated increased susceptibility to SARI-mediated growth inhibition. These findings uncover a novel mode of IFN-induced anti-tumor growth suppression and suggest potential gene therapy applications for SARI.