Abstract
Elevated levels of the immunoregulatory cytokine TGF-β1 in cancer and HIV infection have been linked to the suppression of protective immune responses. The transcriptional regulation of TGF-β1 is complex and still not completely understood. We report here for the first time that the transcription factor GLI2 regulates the expression of TGF-β1 in human CD4(+) T cells. In silico screening revealed five novel putative GLI binding sites in the human TGF-β1 promoter. At least two of these sites within the human TGF-β1 promoter are regulated by the GLI2 activator as knockdown of GLI2 in regulatory CD4(+)CD25(hi) T cells, high producers of TGF-β1, significantly decreased TGF-β1 transcription. Additionally, naïve CD4(+) T cells, low producers of TGF-β1, increased their basal level of TGF-β1 mRNA following lentiviral infection with GLI2. The transcriptional regulation of TGF-β1 by GLI2 is a new extension to Sonic Hedgehog (SHH) and TGF-β1 cross-regulation and may provide insight into the detrimental elevation of TGF-β1 leading to pathogenesis in cancer and HIV infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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CD4-Positive T-Lymphocytes / metabolism*
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Cells, Cultured
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Gene Expression Regulation*
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Genes, Reporter
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HIV Infections / immunology
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HIV Infections / metabolism
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Humans
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Kruppel-Like Transcription Factors / physiology*
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Luciferases, Firefly / biosynthesis
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Luciferases, Firefly / genetics
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Neoplasms / immunology
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Neoplasms / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Promoter Regions, Genetic
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Protein Binding
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Sequence Analysis, DNA
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Transcription, Genetic
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism*
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Zinc Finger Protein Gli2
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tat Gene Products, Human Immunodeficiency Virus / metabolism
Substances
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GLI2 protein, human
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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TGFB1 protein, human
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Transforming Growth Factor beta1
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Zinc Finger Protein Gli2
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tat Gene Products, Human Immunodeficiency Virus
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Luciferases, Firefly