We demonstrated previously γ-globin gene inhibition in K562 cells and primary erythroid progenitors treated with interleukin-6. Although several cis-acting elements have been identified in the globin promoters, the precise mechanism for cytokine-mediated globin gene regulation remains to be elucidated. In this report we demonstrate inhibitors of Stat3 phosphorylation abrogate interleukin-6-mediated γ gene silencing in erythroid cells. DNA-protein binding studies established Stat3 interaction in the 5′-untranslated γ-globin promoter region. Furthermore, co-transfection experiments with Stat3β demonstrate γ promoter inhibition in a concentration-dependent manner, which was significantly reversed when the cognate Stat3-binding site in the 5′-untranslated region was mutated. These studies establish a novel mechanism for γ gene silencing through the STAT signal transduction pathway.
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