Induction of BCL-6 gene expression by interferon-gamma and identification of an IRE in exon I.
BCL-6 is a POZ domain zinc-finger transcription factor that appears to play important roles in the development of the immune system and its regulation. Mutations within BCL-6 gene can therefore contribute to the genesis of a variety of lymphomas, and can also manifest as a classic Th2-type hyperimmune response. In addition to its roles in B- and T-cell development, and in germinal centre formation, the factor is also critical for the development of peripheral memory T cells. In this study, we report that BCL-6 expression is induced by IFN-gamma in Jurkat cells and in nontransformed T cells polarized toward the Th1 phenotype. The IFN-gamma-responsive region has been mapped within the first exon between nucleotide +180 and +200. In vivo footprinting of the first exon reveals that a stretch of DNA between nucleotide +180 to +195 (which we term the X-box) is constitutively occupied in vivo in the presence or absence of IFN-gamma. A guanine at +195 residing at the boundary of the X-box and a downstream IFN-gamma-activated sequence (GAS 1; between nucleotides +192 to +200) is occupied in IFN-gamma-treated cells, indicating the interaction of an IFN-gamma-inducible/modified factor to this region. Consistent with this, electrophoretic mobility shift assays detect STAT-1alpha interactions with the downstream GAS1 motif. The cumulative data suggest that the X-box-binding protein facilitate the binding of STAT-1alpha to the GAS 1 site. The discovery that the BCL-6 transcription factor is inducible by IFN-gamma may help explain some of the postulated biological roles of BCL-6 in T cell development and differentiation, and help explain the Th2-biased phenotype of BCL-6-deficient mice.
Zhou
Gang
G
Department of Immunology, University College London, University of London Institutes of Ophthalmology and Child Health, London, United Kingdom.
Ono
Santa Jeremy
SJ
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D018797:Cell Cycle Proteins; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020382:Interleukin-18 / Q000235:genetics*; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D020382:Interleukin-18; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D014157:Transcription Factors; D007371:Interferon-gamma