RED CELLS, IRON, AND ERYTHROPOIESIS SCF induces -globin gene expression by regulating downstream transcription factor COUP-TFII

Increased fetal hemoglobin expression in adulthood is associated with acute stress erythropoiesis. However, the mechanisms underlying -globin induction during the rapid expansion of adult erythroid progenitor cells have not been fully elucidated. Here, we examined COUP-TFII as a potential repressor of -globin gene after stem cell factor (SCF) stimulation in cultured human adult erythroid progenitor cells. We found that COUP-TFII expression is suppressed by SCF through phosphorylation of serine/threonine phosphatase (PP2A) and correlated well with fetal hemoglobin induction. Furthermore, down-regulation of COUP-TFII expression with small interfering RNA (siRNA) significantly increases the -globin expression during the erythroid maturation. Moreover, SCF-increased expression of NF-YA associated with redox regulator Ref-1 and cellular reducing condition enhances the effect of SCF on -globin expression. Activation of Erk1/2 plays a critical role in SCF modulation of downstream transcriptional factor COUP-TFII, which is involved in the regulation of -globin gene induction. Our data show that SCF stimulates Erk1/2 MAPK signaling pathway, which regulates the downstream repressor COUP-TFII by inhibiting serine/threonine phosphatase 2A activity, and that decreased COUP-TFII expression resulted in -globin reactivation in adult erythropoiesis. These observations provide insight into the molecular pathways that regulate -globin augmentation during stress erythropoiesis. (Blood. 2009;114:187-194)