Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-kappaB sites.

Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.

Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-kappaB sites.

Cancer Res. 2000 Sep 1;60(17):4939-45. Unique Identifier : AIDSLINE MED/20441594
Mori N; Ueda A; Ikeda S; Yamasaki Y; Yamada Y; Tomonaga M; Morikawa S; Geleziunas R; Yoshimura T; Yamamoto N; Department of Preventive Medicine and AIDS Research, Institute of; Tropical Medicine, Nagasaki University, Japan.; n-mori@net.nagasaki-u.ac.jp

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.

Keywords: JOURNAL ARTICLE Binding Sites Enhancer Elements (Genetics)/PHYSIOLOGY Gene Expression Regulation, Viral Gene Products, tax/GENETICS/METABOLISM/*PHYSIOLOGY Human HTLV-I/GENETICS HTLV-I Infections/GENETICS/METABOLISM Jurkat Cells Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated/GENETICS/ VIROLOGY Monocyte Chemoattractant Protein-1/BIOSYNTHESIS/*GENETICS NF-kappa B/GENETICS/METABOLISM/*PHYSIOLOGY Oncogene Proteins v-rel/METABOLISM Promoter Regions (Genetics) Protein Binding RNA, Messenger/BIOSYNTHESIS/GENETICS Signal Transduction/PHYSIOLOGY T-Lymphocytes/METABOLISM/PHYSIOLOGY/VIROLOGY Trans-Activation (Genetics)/*PHYSIOLOGY

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