Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1
Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1
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DOI：
10.1038/sj.onc.1209751
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发表时间：
2006-12-01
期刊：
影响因子：
8
通讯作者：
Richmond, A.
中科院分区：
文献类型：
--
作者：
Amiri, K. I.;Ha, H. C.;Richmond, A.
黑色素瘤细胞持续产生CXC配体1(CXCL1)趋化因子是肿瘤生长的主要效应因子。我们以前已经证明，这种趋化因子的结构性表达依赖于转录因子核因子-kappa B(NF-kappa B)、刺激蛋白-1(SP1)、高迁移率族-I/Y(HMGI/Y)、CAAT置换蛋白(CDP)和多聚(ADPribose)聚合酶-1(PARP-1)。在这项研究中，我们首次证明了CXCL1通过PARP-1在黑色素瘤细胞中转录调控的机制。在非活性状态下，PARP-1以序列特异性的方式与CXCL1启动子结合，并阻止核因子-kappa B(p65/p50)与其元件结合。然而，PARP-1酶活性的激活增强了CXCL1的表达，这是因为PARP1失去了与CXCL1启动子的结合，伴随着p65与启动子的结合增强。阐明核因子-kappa B相互作用因子在可能的CXCL1增强体中的作用，将为制定策略以阻断该趋化因子和其他趋化因子在癌症中的结构性表达和开发靶向治疗提供关键信息。
The continuous production of the CXC ligand 1 ( CXCL1) chemokine by melanoma cells is a major effector of tumor growth. We have previously shown that the constitutive expression of this chemokine is dependent upon transcription factors nuclear factor- kappa B ( NF- kappa B), stimulating protein-1 (SP1), high- mobility group-I/Y ( HMGI/Y), CAAT displacement protein ( CDP) and poly( ADPribose) polymerase- 1 ( PARP-1). In this study, we demonstrate for the first time the mechanism of transcriptional regulation of CXCL1 through PARP-1 in melanoma cells. In its inactive state, PARP- 1 binds to the CXCL1 promoter in a sequence-specific manner and prevents binding of NF- kappa B ( p65/ p50) to its element. However, activation of the PARP- 1 enzymatic activity enhances CXCL1 expression, owing to the loss of PARP1 binding to the CXCL1 promoter, accompanied by enhanced binding of p65 to the promoter. The delineation of the role of NF-kappa B- interacting factors in the putative CXCL1 enhanceosome will provide key information in developing strategies to block constitutive expression of this and other chemokines in cancer and to develop targeted therapy.