Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor
Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor
复制标题
DOI：
10.1038/sj.onc.1202778
复制
发表时间：
1999-07-08
期刊：
影响因子：
8
通讯作者：
Notario, V
中科院分区：
文献类型：
--
作者：
Soldatenkov, VA;Albor, A;Notario, V
尤文氏肉瘤 (EWS) 细胞积累了稳态水平升高的聚 (ADP-核糖) 聚合酶 (PARP) mRNA 和蛋白质。为了了解 PARP 上调的分子机制，我们克隆并分析了 EWS 细胞中 PARP 基因的 5' 侧翼区域。核苷酸序列分析表明 EWS 细胞中 PARP 启动子区域没有变化。 PARP 启动子包含 ETS 转录因子的多个结合基序。我们还观察到，相对于表达较低水平 PARP 的其他人类肿瘤类型细胞，PARP 和 ETS1 的表达协同上调。 EWS 细胞中 ETS1 的瞬时共表达导致 PARP 启动子活性的强烈增强。在用 Ets1 反义 cDNA 构建体稳定转染的 EWS 细胞中，进一步证明了 ETS 参与 PARP 基因表达的调节。反义介导的内源性 ETS1 下调导致 EWS 细胞中 PARP 表达受到抑制，并使这些细胞对电离辐射敏感。这些数据为 ETS 对 PARP 表达水平的调节提供了支持，并表明 ETS 转录因子与 EWS 细胞的辐射反应有关。
Ewing's sarcoma (EWS) cells accumulate elevated steady-state levels of poly (ADP-ribose) polymerase (PARP) mRNA and protein, To understand the molecular mechanisms underlying PARP upregulation, we cloned and analysed the 5'-flanking region of the PARP gene from EWS cells. Nucleotide sequence analysis demonstrated no variations in the PARP promoter region in EWS cells. The PARP promoter encompasses multiple binding motifs for the ETS transcription factor. We have also observed that there is a coordinated up-regulation of the expression of both PARP and ETS1, relative to cells of other human tumor types expressing lower levels of PARP, Transient coexpression of ETS1 in EWS cells resulted in a strong enhancement of PARP-promoter activity. The participation of ETS in the regulation of PARP gene expression was further demonstrated in EWS cells stably transfected with Ets1 antisense cDNA constructs. Antisense-mediated down-regulation of endogenous ETS1 resulted in the inhibition of PARP expression in EWS cells, and sensitized these cells to ionizing radiation. These data provide support for ETS regulation of PARP expression levels, and implicate ETS transcription factors in the radiation response of EWS cells.