IRF-1 transcriptionally upregulates PUMA, which mediates the mitochondrial apoptotic pathway in IRF-1-induced apoptosis in cancer cells.
IRF-1 transcriptionally upregulates PUMA, which mediates the mitochondrial apoptotic pathway in IRF-1-induced apoptosis in cancer cells.
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DOI：
10.1038/cdd.2009.156
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发表时间：
2010-04
影响因子：
12.4
通讯作者：
Yim, J. H.
中科院分区：
文献类型：
--
作者：
Gao, J.;Senthil, M.;Ren, B.;Yan, J.;Xing, Q.;Yu, J.;Zhang, L.;Yim, J. H.
干扰素调节因子-1(IRF-1)是一种转录因子，作为一种肿瘤抑制因子，可引起肿瘤细胞的凋亡。我们研究了IRF-1对胃癌细胞株的诱导凋亡作用。我们在AGS细胞中建立了稳定的克隆，该细胞具有四环素诱导的IRF-1表达系统。我们利用这些克隆和表达IRF-1的重组腺病毒来探讨IRF-1诱导胃癌细胞凋亡的机制。IRF-1的表达导致胃癌细胞系的凋亡，如磷脂酰丝氨酸暴露、caspase-8、caspase-3和Bid的切割以及线粒体细胞色素c的释放。然而，抑制caspase-8和Bid并不抑制细胞凋亡，也不减少caspase-9的裂解和线粒体细胞色素c的释放。我们随后证明IRF-1上调PUMA(p53上调的细胞凋亡调节器)，已知通过内在途径激活细胞凋亡；这可能不依赖于P53。IRF-1结合于PUMA启动子的不同位置，激活PUMA转录。此外，在PUMA基因敲除和基因敲除细胞中，线粒体凋亡的分子标记被消除，磷脂酰丝氨酸暴露显著减少。最后，我们证明了干扰素-γ诱导IRF-1介导的PUMA在癌细胞中的上调。结论：IRF-1可通过上调PUMA的表达，通过内源性途径而非外源性途径诱导细胞凋亡。
Interferon Regulatory Factor-1 (IRF-1) is a transcription factor which acts as a tumor suppressor and causes apoptosis in cancer cells. We evaluated IRF-1 induced apoptosis in gastric cancer cell lines. We established stable clones in AGS cells that have a tetracycline inducible IRF-1 expression system. We used these clones and recombinant adenovirus expressing IRF-1 to explore the mechanism of IRF-1 induced apoptosis in gastric cancer. Expression of IRF-1 causes apoptosis in gastric cancer cell lines as demonstrated by phosphatidylserine exposure and cleavage of caspase-8, caspase-3, and Bid with mitochondrial release of cytochrome c. However, inhibition of caspase-8 and Bid did not inhibit apoptosis and did not decrease cleaved caspase-9 or mitochondrial release of cytochrome c. We then demonstrate that IRF-1 up-regulates PUMA (p53 up-regulated modulator of apoptosis), that is known to activate apoptosis by the intrinsic pathway; this can be p53 independent. IRF-1 binds to distinct sites in the promoter of PUMA and activates PUMA transcription. Moreover, molecular markers of mitochondrial apoptosis are eliminated in PUMA knockout and knockdown cells and phospatidylserine exposure is decreased dramatically. Finally, we demonstrate that IFN-γ induces IRF-1 mediated up-regulation of PUMA in cancer cells. We conclude that IRF-1 can induce apoptosis by the intrinsic pathway independent of the extrinsic pathway by up-regulation of PUMA.
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