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The zinc finger transcription factor Egr-1 is upregulated in arsenite-treated human keratinocytes

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Abstract

Arsenite is a human carcinogen that may induce cancer in skin, liver, kidney, bladder or lung. Arsenite executes its toxic effects by the induction of signaling cascades. In particular, the activation of the stress-induced protein kinase c-Jun N-terminal protein kinase and p38 and the phosphorylation and activation of the transcription factor c-Jun have been linked to the biological effects of arsenite. We analyzed whether arsenite has an impact on the biosynthesis of the zinc finger transcription factor Egr-1. Egr-1 transcription is upregulated following treatment of cells with hormones, cytokines or toxic chemicals, and thus Egr-1 integrates many signaling cascades with changes in gene expression patterns. Here, we show by Western blot experiments that arsenite induces a transient synthesis of Egr-1 in human HaCaT keratinocytes. Egr-1 biosynthesis was activated by arsenite concentrations insufficient for the induction of c-Jun biosynthesis. This arsenite-triggered Egr-1 biosynthesis was completely inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by AG1487, an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor. These results indicate that activation of the EGF receptor as well as stimulation of the mitogen activated/extracellular signal-regulated protein kinase is essential for arsenite-induced upregulation of Egr-1. Moreover, we detected an elevated transcriptional activation potential of the ternary complex factor Elk1, a key transcriptional regulator of serum response element-driven gene transcription. The Egr-1 5′-flanking region contains five serum response elements. Accordingly, we observed an increase in Egr-1 promoter activity as a result of arsenite treatment. The fact that low concentrations of arsenite are sufficient to induce Egr-1 biosynthesis suggests that Egr-1 may be an integral part of arsenite-triggered signaling cascades leading to tumor formation or cell death via alterations of the cellular genetic program.

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Acknowledgements

We thank N.E. Fusenig for his generous gift of HaCaT cells, and Libby Guethlein and Oliver Rössler for critical reading of the manuscript. This work was supported by the “Universität des Saarlandes”.

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  1. Department of Medical Biochemistry and Molecular Biology, Building 44, University of Saarland Medical Center, 66421, Homburg, Germany

    Alia Al-Sarraj & Gerald Thiel

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  1. Alia Al-Sarraj
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  2. Gerald Thiel
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Correspondence to Gerald Thiel.

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Al-Sarraj, A., Thiel, G. The zinc finger transcription factor Egr-1 is upregulated in arsenite-treated human keratinocytes. J Mol Med 82, 530–538 (2004). https://doi.org/10.1007/s00109-004-0545-0

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