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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4282-4290.
Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-07-2889.
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Submitted July 19, 2005
Accepted January 21, 2006
The Wilms' tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene
Christof Dame*, Karin M Kirschner, Katharina V Bartz, Thomas Wallach, Christiane S Hussels, and Holger Scholz
Department of Neonatology, Campus Virchow-Klinikum, Charite - Universitatsmedizin Berlin, Berlin, Germany
Johannes-Muller-Institute of Physiology, Charite - Universitatsmedizin Berlin, Berlin, Germany
* Corresponding author; email: christof.dame{at}charite.de.
The molecular mechanisms for the developmental-stage and tissue-specific regulation of the erythropoietin (Epo) gene are poorly understood. Recent findings indicate a role of the Wilms' tumor suppressor, Wt1, in the formation of the hematopoietic system. Herein, we tested the hypothesis that Wt1 is a transcriptional regulator of the Epo gene. Binding of the transcriptionally competent Wt1(-KTS) isoform to the minimal Epo promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. Under normoxia Epo expression was significantly increased in HEK 293 and HepG2 cells with forced expression of Wt1(-KTS). A reporter construct harboring the 117-bp minimal human Epo promoter was activated up to 20-fold by transient co-transfection of Wt1(-KTS) in different cell lines. Mutation of the Wt1 binding site in the Epo promoter abrogated this stimulatory effect of the Wt1(-KTS) protein. Hepatic Epo mRNA expression was significantly reduced in embryonic mice with homozygous Wt1 deletion. Furthermore, Wt1 and Epo were co-localized in hepatocytes of the liver and in neuronal cells of the dorsal root ganglia in developing mice. Both proteins were also detected in Sertoli cells of the adult murine testis. In conclusion, we identified Wt1(-KTS) as a novel transcriptional activator for the tissue-specific expression of the Epo gene.
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