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首页> 外文期刊>Life sciences >The egr-1 gene is induced by DNA-damaging agents and non-genotoxic drugs in both normal and neoplastic human cells.
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The egr-1 gene is induced by DNA-damaging agents and non-genotoxic drugs in both normal and neoplastic human cells.

机译：在正常和赘生性人类细胞中，egr-1基因均由DNA破坏剂和非遗传毒性药物诱导。

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The human egr-1 gene encodes a zinc finger transcription factor induced by endogenous and exogenous stimuli such as growth factors, cytokines, and mitogens. Egr-1 regulates other genes involved in growth and differentiation. The present study investigated the influence of genotoxic agents, such as chemotherapy drugs and other DNA damaging agents, on egr-1 expression in normal and neoplastic cells. A transcriptional fusion between the human egr-1 promoter and the enhanced green fluorescent protein (EGFP) gene was used for direct visualization of intracellular Egr-1 regulation. The transcriptional activity of the egr-1 promoter in this reporter system faithfully reflects intrinsic egr-1 expression and induction, as demonstrated by FACS analysis of fluorescence and by RT-PCR for egr-1. EGFP was expressed under the control of the egr-1 promoter in stably transfected immortalized cell lines, such as HEK293, T98G, LNZ308, and 9L, which were then treated with genotoxic agents.A multitude of DNA damaging agents and therapeutic drugs caused significant upregulation of egr-1 transcription. Furthermore, cytotoxic compounds without a direct DNA damaging effect, such as resveratrol and vincristine, which interfere with DNA replication and cell division, were also able to activate egr-1 transcription. This suggests that cell cycle arrest rather than DNA damage seems to be the condition triggering egr-1 transcription. Moreover, treatment with the MAP kinase (MAPK) inhibitor SB203580, which specifically blocks the stress inducible p38/SAPK2 pathway, did not alter egr-1 induction. On the other hand, treatment with the inhibitor PD98059, which specifically blocks the MAPK/ERK pathway, partially suppressed the induction effect. In addition, the egr-1 induction effect caused by genotoxic stress was found to be at least in part independent from the cellular p53 status, as it was observed in p53-deficient as well as in wild type p53 cell lines.These results suggest that induction of egr-1, a gene to which until now no relation to DNA repair has been assigned, may belong to the fundamental cellular responses elicited by genotoxic and mitotic stress in normal as well as in neoplastic cells, and that enhanced levels of Egr-1 protein may be needed to regulate genes involved in DNA repair, cell survival, and apoptosis.
机译：人类egr-1基因编码由内源性和外源性刺激（例如生长因子，细胞因子和促分裂原）诱导的锌指转录因子。 Egr-1调节与生长和分化有关的其他基因。本研究调查了遗传毒性剂，例如化学疗法药物和其他DNA破坏剂，对正常和肿瘤细胞中egr-1表达的影响。人类egr-1启动子和增强型绿色荧光蛋白（EGFP）基因之间的转录融合用于细胞内Egr-1调节的直接可视化。 egr-1启动子在此报告系统中的转录活性如实反映了内在的egr-1表达和诱导，如荧光的FACS分析和egr-1的RT-PCR所证明。 EGFP在egr-1启动子的控制下在稳定转染的永生细胞系中表达，例如HEK293，T98G，LNZ308和9L，然后用遗传毒性剂处理。大量的DNA破坏剂和治疗药物引起明显的上调。 egr-1转录。此外，没有直接的DNA破坏作用的细胞毒性化合物，例如白藜芦醇和长春新碱，它们会干扰DNA复制和细胞分裂，也能够激活egr-1转录。这表明细胞周期停滞而不是DNA损伤似乎是触发egr-1转录的条件。此外，用MAP激酶（MAPK）抑制剂SB203580特异性阻断应激诱导的p38 / SAPK2途径进行的治疗不会改变egr-1的诱导作用。另一方面，用特异性阻断MAPK / ERK途径的抑制剂PD98059进行的治疗可部分抑制诱导作用。此外，由于在缺乏p53的细胞以及野生型p53细胞中都观察到了由基因毒性胁迫引起的egr-1诱导作用至少部分与细胞p53状态无关。迄今为止，尚未确定与DNA修复相关的基因egr-1的诱导可能属于正常和赘生性细胞中由遗传毒性和有丝分裂应激引起的基本细胞应答，并且Egr-水平升高可能需要1种蛋白质来调节涉及DNA修复，细胞存活和凋亡的基因。

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