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EGR-1 enhances tumor growth and modulates the effect of the Wilms' tumor 1 gene products on tumorigenicity

Oncogene volume 19, pages 791–800 (2000)Cite this article

Abstract

The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-finger family and is homozygously mutated or deleted in a subset of Wilms' tumors. Through alternative mRNA splicing, the gene is expressed as four main polypeptides that differ by a stretch of 17 amino acids just N-terminal of the four zinc-fingers and three amino acids between zinc fingers 3 and 4. We have previously shown that expression of the WT1(−/−) isoform, lacking both inserts, increases the tumor growth rate of the adenovirus-transformed baby rat kidney (AdBRK) cell line 7C3H2, whereas expression of the WT1(−/+) isoform, lacking the 17aa insert, strongly suppresses the tumorigenic phenotype. In the present study we show that expression of these splice variants does not affect the tumorigenic potential of the similar AdBRK cell line, 7C1T1. In contrast to the 7C3H2 cell line, this AdBRK cell line expresses high endogenous levels of EGR-1 (early growth response-1) protein, a transcription factor structurally related to WT1. Ectopic expression of EGR-1 in the 7C3H2 AdBRK cells significantly increases their in vivo growth rate and nullifies the tumor suppressor activity of the WT1(−/+) protein. Furthermore, we find that EGR-1 levels are elevated in some Wilms' tumors. These data are the first to show that EGR-1 overexpression causes enhanced tumor growth and that WT1 and EGR-1 exert antagonizing effects on growth regulation in baby rat kidney cells, which might reflect the situation in some Wilms' tumors.

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Acknowledgements

This work was supported by a grant from the Dutch Cancer Society (RUL 95-1044). The authors thank Dr Vikas Sukhatme for generously providing the EGR-1 expression constructs, Dr Veronica van Heyningen for tumor material and Dr Wilhelm Aicher for the human EGR-1 cDNA.

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Centre for Biomedical Genetics, Laboratory of Molecular Carcinogenesis, Leiden University Medical Center, P.O. Box 9503, Leiden, 2300 RA, The Netherlands

    Volkher Scharnhorst, Aswin L Menke, Joline Attema, Johan Klein Haneveld, Nicole Riteco, Alex J van der Eb & Aart G Jochemsen

  2. Department of Experimental Urology, Erasmus University, The Netherlands

    Gert J van Steenbrugge

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  1. Volkher Scharnhorst
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  2. Aswin L Menke
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Scharnhorst, V., Menke, A., Attema, J. et al. EGR-1 enhances tumor growth and modulates the effect of the Wilms' tumor 1 gene products on tumorigenicity. Oncogene 19, 791–800 (2000). https://doi.org/10.1038/sj.onc.1203390

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