The Wilms’ tumor suppressor Wt1 activates transcription of the erythropoietin receptor in hematopoietic progenitor cells Karin M. Kirschner * , Patricia Hagen * , Christiane S. Hussels † , Matthias Ballmaier ‡ , Holger Scholz * ,1 and Christof Dame † ,1 ,2 * Institut für Vegetative Physiologie and † Department of Neonatology, Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Berlin, Germany; and ‡ Department of Pediatric Hematology and Oncology, Medizinische Hochschule, Hannover, Germany 2 Correspondence: Department of Neonatology, Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: christof.dame@charite.de The Wilms’ tumor protein Wt1 is required for embryonic development and has been implicated in hematologic disorders. Since Wt1 deficiency may compromise the proliferation and differentiation of erythroid progenitor cells, we analyzed the possible role of the transcriptionally active Wt1 isoform, Wt1(–KTS), in regulating the expression of the erythropoietin receptor (EpoR). Wt1 and EpoR were coexpressed in CD117 + hematopoietic progenitor cells and in several hematopoietic cell lines. CD117 + cells of Wt1 -deficient murine embryos ( Wt1 – / – ) exhibited a significantly lower proliferation response to recombinant erythropoietin than CD117 + cells of heterozygous ( Wt1 +/ – ) and wild-type littermates ( Wt1 +/+ ). EpoR expression was significantly diminished in hematopoietic progenitors (CD117 + ) that lacked Wt1 , and the erythroid colony-forming capacity was reduced by more than 50% in fetal liver cells of Wt1 -deficient embryonic mice. Wt1(–KTS) significantly increased endogenous EpoR transcripts in transfected cells. The proximal EpoR promoter of human and mouse was stimulated more than 10-fold by Wt1(–KTS) in transiently cotransfeced K562 erythroleukemia cells. A responsible cis -element, which is highly conserved in the EpoR promoter of human and mouse, was identified by mutation analysis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. In conclusion, activation of the EpoR gene by Wt1 may represent an important mechanism in normal hematopoiesis.—Kirschner, K. M., Hagen, P., Hussels, C. S., Ballmaier, M., Scholz, H., Dame, C. The Wilms’ tumor suppressor Wt1 activates transcription of the erythropoietin receptor in hematopoietic progenitor cells. Key Words: erythropoiesis • colony-forming unit-erythroid • gene expression • development • oncogene
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The Wilms tumor suppressor Wt1 activates transcription of the erythropoietin receptor in hematopoietic progenitor cells
Kirschner, Karin M.; Hagen, Patricia; Hussels, Christiane S.; Ballmaier, Matthias; Scholz, Holger; Dame, Christof
Follow The FASEB Journal
, Volume 22 (8): 2690
Fed of American Socs for Experimental Biology – Aug 1, 2008
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