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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1917-1922.
Prepublished online as a Blood First Edition Paper on October 19, 2006; DOI 10.1182/blood-2006-08-044172.
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Submitted August 28, 2006
Accepted October 8, 2006
Ape1 regulates hematopoietic differentiation of embryonic stem cells through its redox functional domain
Gang-Ming Zou, Mei-Hua Luo, April Reed, Mark R. Kelley, and Mervin C. Yoder*
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
Department of Pediatrics, Section of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
* Corresponding author; email: myoder{at}iupui.edu.
Ape1 is a molecule with dual functions in DNA repair and redox regulation of transcription factors. In Ape1 deficient mice, embryos do not survive beyond embryonic day 9, indicating that this molecule is required for normal embryo development. Currently, direct evidence of the role of Ape1 in regulating hematopoiesis is lacking. We used the ES cell differentiation system to generate hematopoietic cells and a siRNA approach to knock down Ape1 gene expression to test the role of Ape1 in hematopoiesis. We have determined that hemangioblast development from ES cells was reduced 2 to 3 fold when Ape1 gene expression was knocked down by Ape1 specific siRNA. Furthermore, both primitive and definitive hematopoiesis were also significantly diminished when Ape1 expression was knocked down. Impaired hematopoiesis was not associated with increased apoptosis in siRNA treated cells. To begin to explore the mechanism whereby Ape1 regulates hematopoiesis, we found that inhibition of the redox activity of Ape1 with E3330, a specific Ape1 redox inhibitor, but not Ape1 DNA repair activity which was blocked using the small molecule, methoxyamine, affected cytokine-mediated hemangioblast development in vitro. In summary, these data indicate Ape1 is required in normal embryonic hematopoiesis and that the redox, but not the repair endonuclease function of Ape1 is critical in normal embryonic hematopoietic development.
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