Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Base Sequence
-
CD28 Antigens / analysis
-
CD28 Antigens / genetics
-
Cell Transformation, Viral / genetics
-
Cell Transformation, Viral / immunology*
-
DNA-Binding Proteins / analysis
-
DNA-Binding Proteins / antagonists & inhibitors
-
DNA-Binding Proteins / biosynthesis*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Gene Expression Regulation / immunology
-
Gene Products, tax / antagonists & inhibitors
-
Gene Products, tax / physiology
-
Human T-lymphotropic virus 1 / immunology*
-
Humans
-
I-kappa B Proteins*
-
Interferon Regulatory Factors
-
Jurkat Cells
-
Lymphocyte Activation / genetics
-
Lymphocyte Activation / immunology*
-
Molecular Sequence Data
-
Mutagenesis, Site-Directed
-
NF-kappa B / antagonists & inhibitors
-
NF-kappa B / metabolism
-
NFATC Transcription Factors
-
Nuclear Proteins*
-
Promoter Regions, Genetic / immunology
-
Protein Structure, Tertiary / genetics
-
Response Elements / immunology
-
Sp1 Transcription Factor / analysis
-
Sp1 Transcription Factor / genetics
-
T-Lymphocyte Subsets / immunology*
-
T-Lymphocyte Subsets / metabolism*
-
T-Lymphocyte Subsets / virology
-
Transcription Factors / analysis
-
Transcription Factors / antagonists & inhibitors
-
Transcription Factors / biosynthesis*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
Substances
-
CD28 Antigens
-
DNA-Binding Proteins
-
Gene Products, tax
-
I kappa B beta protein
-
I-kappa B Proteins
-
Interferon Regulatory Factors
-
NF-kappa B
-
NFATC Transcription Factors
-
Nuclear Proteins
-
Sp1 Transcription Factor
-
Transcription Factors
-
interferon regulatory factor-4