title: Transcriptional activation of the vascular cell adhesion molecule-1 gene in T lymphocytes expressing human T-cell leukemia virus type 1 Tax protein.
abstract: Recruitment and extravasation of T cells through the blood-brain barrier are favored by adhesion molecule-mediated interactions of circulating T cells with endothelial cells. Since a common pathological finding in human T-cell leukemia virus type 1 (HTLV-1)-associated diseases is the infiltration of HTLV-1-infected T lymphocytes into various organs, we have looked for the profile of adhesion molecules expressed by HTLV-1-transformed T cells. Flow cytometry analysis indicated that these cells were expressing high levels of vascular cell adhesion molecule 1 (VCAM-1 [CD106]), a 110-kDa member of the immunoglobulin gene superfamily, first identified on endothelial cells stimulated with inflammatory cytokines. This adhesion molecule was also expressed by T cells obtained from one patient with HTLV-1-associated myelopathy/tropical spastic paraparesis but not by activated T cells isolated from one normal blood donor. The role of the viral trans-activator Tax protein in the induction of VCAM-1 was first indicated by the detection of this adhesion molecule on Jurkat T-cell clones stably expressing the tax gene. The effect of Tax on VCAM-1 gene transcription was next confirmed in JPX-9 cells, a subclone of Jurkat cells, carrying the tax sequences under the control of an inducible promoter. Furthermore, deletion and mutation analyses of the VCAM-1 promoter performed with chloramphenicol acetyltransferase constructs revealed that Tax was trans activating the VCAM-1 promoter via two NF-kappaB sites present at bp -72 and -57 in the VCAM-1 gene promoter, with both of them being required for the Tax-induced expression of this adhesion molecule. Finally, gel mobility shift assays demonstrated the nuclear translocation of proteins specifically bound to these two NF-kappaB motifs, confirming that VCAM-1 was induced on Tax-expressing cells in a kappaB-dependent manner. Collectively, these results therefore suggest that the exclusive Tax-induced expression of VCAM-1 on T cells may represent a pivotal event in the progression of HTLV-1-associated diseases.
authors.affiliation: Immuno-Virologie Moléculaire et Cellulaire (UMR 5537), CNRS-UCB Lyon I, Faculté de Médecine Lyon-RTH, Laennec, France.
authors.forename: H
authors.initials: H
authors.lastname: Valentin
authors.forename: I
authors.initials: I
authors.lastname: Lemasson
authors.forename: S
authors.initials: S
authors.lastname: Hamaia
authors.forename: H
authors.initials: H
authors.lastname: Cassé
authors.forename: S
authors.initials: S
authors.lastname: König
authors.forename: C
authors.initials: C
authors.lastname: Devaux
authors.forename: L
authors.initials: L
authors.lastname: Gazzolo
mesh_terms: D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000502:physiology*; D015490:HTLV-I Infections / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000235:genetics; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D014158:Transcription, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
chemical_list: D016356:Gene Products, tax; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1