Stat3 beta inhibits gamma-globin gene expression in erythroid cells.
We demonstrated previously gamma-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 gamma gene silencing in erythroid cells. DNA-protein binding studies established Stat3 interaction in the 5'-untranslated gamma-globin promoter region. Furthermore, co-transfection experiments with Stat3 beta demonstrate gamma 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 gamma gene silencing through the STAT signal transduction pathway.
Foley
Heather A
HA
Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama 36688, USA.
Ofori-Acquah
Solomon F
SF
Yoshimura
Akihiko
A
Critz
Stuart
S
Baliga
B Surendra
BS
Pace
Betty S
BS
D020121:5' Untranslated Regions / Q000235:genetics; D000209:Acute-Phase Proteins / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics*; D005914:Globins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000494:pharmacology*; D020014:K562 Cells; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D020121:5' Untranslated Regions; D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D005914:Globins