A signaling mechanism for growth-related expression of fetal hemoglobin.
Increases in fetal hemoglobin have been identified after birth in several clinical settings associated with stressed or malignant erythropoiesis. To better understand the relationship between the expression of this fetal protein and growth, donated human erythroid progenitor cells were cultured in the presence of erythropoietin (EPO) plus the growth-modifying cytokine stem cell factor (SCF), and several growth-related signaling pathways were interrogated. Only the MEK1/2 inhibitor (PD98059) demonstrated significant effects on fetal hemoglobin. In the absence of PD98059, levels of fetal hemoglobin averaged 27.4% +/- 7.9% in EPO+SCF compared with 1.26% +/- 1.7% in EPO alone (P =.02). A linear dose response in levels of fetal hemoglobin to PD98059 was detected (0.16 microM = 27.13%, 0.8 microM = 19.6%, 4 microM = 12.2%, 20 microM = 1.54%). Western blot analyses revealed that SCF was required for phosphorylation of MEK and p44MAPK in this setting, and quantitative polymerase chain reaction demonstrated a significant increase in gamma-globin mRNA. Particular perturbations of growth-related signaling may also function to activate tissue-specific genes normally expressed during fetal development. This concept may be relevant for the development of new treatment rationales for beta hemoglobinopathies.
Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Natarajan V
NV
Bhanu
Tiffany A
TA
Trice
Y Terry
YT
Lee
Jeffery L
JL
Miller
D018952:Antigens, CD34 / Q000096:biosynthesis; D002455:Cell Division; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D005914:Globins / Q000378:metabolism; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013997:Time Factors
D018952:Antigens, CD34; D004791:Enzyme Inhibitors; D005419:Flavonoids; D012333:RNA, Messenger; D019089:Stem Cell Factor; D004921:Erythropoietin; D005914:Globins; D005319:Fetal Hemoglobin; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one