Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53
Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53
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DOI：
10.1158/0008-5472.can-04-3742
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Mercola, D
中科院分区：
文献类型：
--
作者：
Krones-Herzig, A;Mittal, S;Mercola, D
早期生长反应 1 (Egr1) 基因是一种转录因子，既充当肿瘤抑制因子又充当肿瘤启动子。 Egr1缺失的小鼠胚胎成纤维细胞绕过复制衰老，表现出DNA损伤反应的丧失和明显的永生生长，表明p53功能的丧失。严格的表达分析显示，Egr1 缺失的小鼠胚胎成纤维细胞中有 266 个转录物具有 > 2 倍的差异表达，其中包括 143 个已知基因。在 143 个基因中，程序辅助搜索发现了 66 个与 Egr1 相关的信息丰富的基因。所有 66 个基因都可以放置在一个由已知 Egr1 靶基因的三个分支点组成的单一调控网络上：TGF beta.1、IL6 和 IGFI。此外，还鉴定了 19 个作为 p53 已知靶标的基因，表明 p53 是第四个分支点。电泳迁移率变动分析以及染色质免疫沉淀证实 p53 是 Egr1 的直接靶标。由于 p53 表达缺陷会导致小鼠出现肿瘤，因此我们在一项两步皮肤癌发生研究（144 只小鼠）中测试了 Egr1 的作用，结果显示 Egr1 缺失的小鼠皮肤肿瘤的发展一致加速（P < 0.005）。这些研究揭示了 Egr1 作为体内肿瘤抑制因子的新作用。
The early growth response 1 (Egr1) gene is a transcription factor that acts as both a tumor suppressor and a tumor promoter. Egr1-null mouse embryo fibroblasts bypass replicative senescence and exhibit a loss of DNA damage response and an apparent immortal growth, suggesting loss of p53 functions. Stringent expression analysis revealed 266 transcripts with > 2-fold differential expression in Egr1-null mouse embryo fibroblasts, including 143 known genes. Of the 143 genes, program-assisted searching revealed 66 informative genes linked to Egr1. All 66 genes could be placed on a single regulatory network consisting of three branch points of known Egr1 target genes: TGF beta.1, IL6, and IGFI. Moreover, 19 additional genes that are known targets of p53 were identified, indicating that p53 is a fourth branch point. Electrophoretic mobility shift assay as well as chromatin immunoprecipitation confirmed that p53 is a direct target of Egr1. Because deficient p53 expression causes tumors in mice, we tested the role of Egr1 in a two-step skin carcinogenesis study (144 mice) that revealed a uniformly accelerated development of skin tumors in Egr1-null mice (P < 0.005). These studies reveal a new role for Egr1 as an in vivo tumor suppressor.