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首页> 外文期刊>Molecular and Cellular Biology >An Arf-Egr-C/EBPβ Pathway Linked to Ras-Induced Senescence and Cancer
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An Arf-Egr-C/EBPβ Pathway Linked to Ras-Induced Senescence and Cancer

机译：与Ras诱导的衰老和癌症相关的Arf-Egr-C /EBPβ途径

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Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19Arf or other tumor suppressors can be transformed. The transcription factor C/EBPβ is required for OIS in primary fibroblasts but is downregulated by H-RasV12 in immortalized NIH 3T3 cells through a mechanism involving p19Arf loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3Ras cells and directly and redundantly control Cebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in the Cebpb promoter and associate transiently with this region after serum stimulation, coincident with Cebpb induction. Codepletion of all three Egrs prevented Cebpb expression, and serum induction of Egrs was significantly blunted in 3T3Ras cells. Egr2 and Egr3 levels were also reduced in RasV12-expressing p19Arf null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf-deficient but not wild-type (WT) MEFs, leading to Cebpb downregulation. Analysis of human cancers revealed a strong correlation between EGR levels and CEBPB expression, regardless of whether CEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines induced CEBPB and inhibited proliferation. Thus, our findings identify the Arf-Egr-C/EBPβ axis as an important determinant of cellular responses (senescence or transformation) to oncogenic Ras signaling.
机译：癌基因诱导的衰老（OIS）可保护正常细胞免受 Ras 的转化，而缺乏p14 / p19 Arf 或其他肿瘤抑制因子的细胞可以被转化。转录因子C /EBPβ是原代成纤维细胞中OIS所必需的，但通过一种机制，H- Ras V12 可以通过一种机制下调其转录水平涉及p19 Arf 丢失。在这里，我们报道血清诱导的早期生长反应（Egr）蛋白家族的成员在3T3 Ras 细胞中也被下调，并直接和冗余地控制 Cebpb 基因转录。 Egr1，Egr2和Egr3识别 Cebpb 启动子中的三个位点，并在血清刺激后与该区域短暂关联，与 Cebpb 诱导相符。三种Egrs的完全编码均阻止了 Cebpb 表达，并且3T3 Ras 细胞中Egrs的血清诱导明显减弱。在表达Ras V12 的p19 Arf 空小鼠胚胎成纤维细胞（MEFs）中，Egr2和Egr3的水平也降低了，而在缺乏Arf的小鼠中，总的Egr DNA结合活性受到抑制。而不是野生型（WT）MEF，从而导致 Cebpb 下调。对人类癌症的分析显示，无论肿瘤中 CEBPB 是升高还是降低， EGR 水平和 CEBPB 表达之间都存在着很强的相关性。此外，Egrs在肿瘤细胞系中的过度表达诱导 CEBPB 并抑制增殖。因此，我们的发现将Arf-Egr-C /EBPβ轴确定为对致癌Ras信号的细胞应答（衰老或转化）的重要决定因素。

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