ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells.
ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells.
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DOI：
10.1093/nar/gku929
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发表时间：
2014-10-29
影响因子：
14.9
通讯作者：
Hollenhorst PC
中科院分区：
文献类型：
--
作者：
Plotnik JP;Budka JA;Ferris MW;Hollenhorst PC
RAS/ERK通路通常在癌中被激活，并通过改变转录程序促进肿瘤发生。然而，介导这些转录变化的顺式调控元件和反式作用因子的阵列仍然不清楚。我们的全基因组分析确定，由邻近ETS和AP-1转录因子结合位点组成的序列在上皮细胞中被RAS/ERK信号激活的细胞迁移基因附近富集。候选ETS蛋白的体内筛选揭示了ETS 1是RAS/ERK激活细胞迁移所特异性需要的。此外，通过ETS/AP-1的迁移和转录激活都需要ETS 1的ERK磷酸化。多个ETS蛋白的全基因组定位表明，ETS 1特异性结合增强子ETS/AP-1序列。ETS 1占有率及其在细胞迁移中的作用在来自多种组织的上皮细胞中是保守的，与上皮细胞系常见的染色质组织一致。全基因组表达分析表明，ETS 1是激活RAS调节的细胞迁移基因所必需的，但也确定了ETS 1在抑制基因如DUSP 4、DUSP 6和SPRY 4中的惊人作用，这些基因为RAS/ERK通路提供负反馈。因此，ETS 1是RAS/ERK通路激活所必需的。因此，ETS 1在介导上皮特异性RAS/ERK转录功能中具有双重作用。
The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells. In vivo screening of candidate ETS proteins revealed that ETS1 is specifically required for migration of RAS/ERK activated cells. Furthermore, both migration and transcriptional activation through ETS/AP-1 required ERK phosphorylation of ETS1. Genome-wide mapping of multiple ETS proteins demonstrated that ETS1 binds specifically to enhancer ETS/AP-1 sequences. ETS1 occupancy, and its role in cell migration, was conserved in epithelial cells derived from multiple tissues, consistent with a chromatin organization common to epithelial cell lines. Genome-wide expression analysis showed that ETS1 was required for activation of RAS-regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway. Consistently, ETS1 was required for robust RAS/ERK pathway activation. Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions.
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影响因子：
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通讯作者：
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