Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells.
IFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTLV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-kappaB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the kappaB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the -617 to -209 region of the IRF-4 promoter. Furthermore, mutation of either the kappaB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4(+) T lymphocytes.
Sharma
Sonia
S
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
Grandvaux
Nathalie
N
Mamane
Yael
Y
Genin
Pierre
P
Azimi
Nazli
N
Waldmann
Thomas
T
Hiscott
John
J
D001483:Base Sequence; D018106:CD28 Antigens / Q000032:analysis / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D016356:Gene Products, tax / Q000037:antagonists & inhibitors / Q000502:physiology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins; D050835:Interferon Regulatory Factors; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D020218:Response Elements / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000032:analysis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C083487:I kappa B beta protein