Transcriptional control of human T-BET expression: the role of Sp1.
Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-gamma gene expression in NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-gamma secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-gamma protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-gamma are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/or treating diseases associated with aberrant T-BET or IFN-gamma expression.
Yu
Jianhua
J
Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. Jianhua.yu@osumc.edu
Wei
Min
M
Boyd
Zachary
Z
Lehmann
Esther B
EB
Trotta
Rossana
R
Mao
Hsiaoyin
H
Liu
Shujun
S
Becknell
Brian
B
Jaung
Michael S
MS
Jarjoura
David
D
Marcucci
Guido
G
Wu
Lai-Chu
LC
Caligiuri
Michael A
MA
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016415:Sequence Alignment; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D000098815:T-bet Transcription Factor
D016329:Sp1 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; C066851:mithramycin A; D008926:Plicamycin