| Signal transducer and activator of transcription 3 has been implicated in a wide range of biological effects, and is particularly relevant in the process of globin gene switching. It has been previously demonstrated that IL-6 preferentially activates Stat3β in K562 cells and appears to be the major STAT protein in IL-6-mediated megakaryocytic differentiation. Although several putative STAT binding elements have been identified in the globin promoters, the precise mechanism for cytokine-mediated regulation of the β-like globin genes has not yet been fully characterized. In this project DNA-protein binding studies established Stat3 interaction with the 5′-untranslated regions of the β-like globin genes. Furthermore, mutation experiments confirmed the area of activity through which Stat3β mediates its repression of the γ globin gene to be in the 5′-untranslated region, containing the Stat3 site. Co-transfection experiments with Stat3β demonstrated inhibition of ϵ and β promoter activity as well. Lastly, over-expression of Stat3β repressed endogenous γ globin mRNA levels in erythroid cells. In conclusion, this study identified Stat3 as a silencer protein of the β-like globin genes. |
