SCF induces gamma-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 gamma-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 gamma-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 gamma-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 gamma-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 gamma-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 gamma-globin reactivation in adult erythropoiesis. These observations provide insight into the molecular pathways that regulate gamma-globin augmentation during stress erythropoiesis.
Aerbajinai
Wulin
W
Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-2560, USA.
Zhu
Jianqiong
J
Kumkhaek
Chutima
C
Chin
Kyung
K
Rodgers
Griffin P
GP
D000328:Adult; D001483:Base Sequence; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology*; D013312:Stress, Physiological; D015533:Transcriptional Activation / Q000187:drug effects; D055545:gamma-Globins / Q000235:genetics*
D023081:CCAAT-Binding Factor; D051837:COUP Transcription Factor II; D017931:DNA Primers; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D054648:Protein Phosphatase 2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D055545:gamma-Globins; C492061:NFYA protein, human; C085108:APEX1 protein, human; C095569:NR2F2 protein, human