title: GLI2 regulates TGF-β1 in human CD4+ T cells: implications in cancer and HIV pathogenesis.
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.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David E Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Furler
authors.forename: Christel H
authors.initials: CH
authors.lastname: Uittenbogaart
mesh_terms: D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D000075746:Zinc Finger Protein Gli2; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D000075746:Zinc Finger Protein Gli2; D054322:tat Gene Products, Human Immunodeficiency Virus; D049409:Luciferases, Firefly