Human T cell leukemia virus type I Tax and phorbol 12-myristate 13-acetate induce expression of the A20 zinc finger protein by distinct mechanisms involving nuclear factor kappa B.
A20 was originally identified as a primary tumor necrosis factor alpha (TNF)-responsive gene, which encodes a 790-amino acid zinc finger protein. A20 is expressed in a wide variety of cell lines, including fibroblasts, in which A20 expression protects cells from TNF cytotoxicity. An analysis of A20 expression in lymphocytic and monocytic cells lines revealed that A20 protein expression correlates with lymphocyte activation and monocyte differentiation. A20 expression was also induced in Jurkat T cells expressing the human T cell leukemia virus type I Tax protein. Transient transfection studies demonstrated that stimulation of A20 transcription by TNF, phorbol 12-myristate 13-acetate (PMA), and Tax was mediated by two kappa B elements within the A20 promoter. Accordingly, DNA electrophoretic mobility shift assays confirmed inducible binding of nuclear factor kappa B (NF-kappa B) to a promoter fragment containing both A20 kappa B elements. Analysis of individual A20 kappa B sites revealed that both kappa B sites were required for TNF or PMA activation of the A20 promoter; however, Tax activation required only one kappa B site. Overexpression of NF-kappa B subunits activated the wild type A20 promoter, but did not activate mutated forms containing single kappa B sites. Thus, Tax activation of A20 transcription occurs through a mechanism distinct from PMA and TNF, possibly due to differential activation of NF-kappa B complexes or transcriptional cofactors.
Laherty
C D
CD
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Perkins
N D
ND
Dixit
V M
VM
D001483:Base Sequence; D002460:Cell Line; D002461:Cell Line, Transformed; D004247:DNA; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D016356:Gene Products, tax / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016335:Zinc Fingers / Q000235:genetics*
D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D013755:Tetradecanoylphorbol Acetate