title: Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-kappaB sites.
abstract: Infection by human T-cell leukemia virus type (HTLV) I leads to adult T-cell leukemia and is also associated with the neurodegenerative disease HTLV-I-associated myelopathy/tropical spastic paraparesis. Leukocytes are attracted to sites of inflammation by chemokines. One such chemokine is monocyte chemoattractant protein (MCP)-1, a member of the C-C subfamily of chemokines. We investigated whether HTLV-I infection causes up-regulation of MCP-1, which may in turn cause recruitment of leukocytes to HTLV-I-infected areas. We now report that MCP-1 mRNA levels are elevated in HTLV-I-infected T-cell lines, when compared with uninfected ones. We further confirmed secretion of MCP-1 by HTLV-I-infected T-cell lines. MCP-1 mRNA was also expressed in leukemic cells from patients with adult T-cell leukemia. The 5' transcriptional regulatory region of the MCP-1 gene was activated by the HTLV-I-encoded transactivator Tax in the human T-cell line Jurkat, in which endogenous MCP-1 is induced by Tax. By using site-specific point mutations, we have identified two closely spaced nuclear factor (NF)-kappaB sites, A1 and A2, to be important for Tax-mediated transactivation of the MCP-1 gene. Through the use of an electrophoretic mobility shift assay, we demonstrated that Tax induced NF-kappaB binding to both MCP-1 kappaB sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-kappaB. Our results thus reveal how Tax disrupts the normally regulated MCP-1 gene and leads to its constitutive expression in HTLV-I-infected cells. These findings may have important implications for our understanding of HTLV-I-associated diseases.
authors.affiliation: Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Japan. n-mori@net.nagasaki-u.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Mori
authors.forename: A
authors.initials: A
authors.lastname: Ueda
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Tomonaga
authors.forename: S
authors.initials: S
authors.lastname: Morikawa
authors.forename: R
authors.initials: R
authors.lastname: Geleziunas
authors.forename: T
authors.initials: T
authors.lastname: Yoshimura
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D001665:Binding Sites; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020572:Oncogene Proteins v-rel / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology / Q000821:virology; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D018932:Chemokine CCL2; D016356:Gene Products, tax; D016328:NF-kappa B; D020572:Oncogene Proteins v-rel; D012333:RNA, Messenger