Transcriptional activation of the interleukin-21 gene and its receptor gene by human T-cell leukemia virus type 1 Tax in human T-cells.
At the incipient stages of the development of adult T-cell leukemia, T-cells infected with human T-cell leukemia virus type 1 (HTLV-1) suffer disregulation in cell growth caused by aberrant expression of host genes by the HTLV-1 transactivator protein Tax (Tax1). Tax1-mediated growth promotion is thought to result from, at least in part, up-regulation of genes for growth factors and their receptors that induce T-cell growth. In the present study, we demonstrate that Tax1 transactivates the interleukin-21 (IL-21) and its receptor (IL-21R) genes in human T-cells. Introduction of Tax1 via recombinant adenoviruses induced expression of endogenous IL-21 and IL-21R. Isolated promoters of the IL-21 and IL-21R genes were activated by Tax1 in reporter assays, which further revealed that there were at least two Tax1-responsive elements in either the IL-21 promoter or the IL-21R promoter. Chromatin immunoprecipitation assay and gel mobility shift assay exhibited that the IL-21 promoter elements bound transcription factors AP-1 and NF-kappaB, and the IL-21R promoter elements were associated with AP-1 and interferon regulatory factor. Collectively, Tax1-dependent activation of these transcriptional factors presumably contributes to expression of the IL-21 gene and its receptor gene. The related virus HTLV-2 with Tax2 similar to Tax1 is known not to be pathogenic. Tax2 exhibited little, if any, or no induction of the IL-21 transcription in CD4+ T-cells, in contrast to Tax1. The study suggests insights into cytokine-dependent aberrant growth of HTLV-1-infected T-cells and the molecular basis of different pathogenicity between HTLV-1 and HTLV-2.
Mizuguchi
Mariko
M
Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Asao
Hironobu
H
Hara
Toshifumi
T
Higuchi
Masaya
M
Fujii
Masahiro
M
Nakamura
Masataka
M
D000256:Adenoviridae; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D015367:Human T-lymphotropic virus 2 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D053738:Interleukin-21 Receptor alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D000098546:Interleukin-21
D016356:Gene Products, tax; C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C514970:tax protein, Human T-lymphotrophic virus 1; C514971:tax protein, Human T-lymphotrophic virus 2; D000098546:Interleukin-21