REGULATION OF LYMPHOTOXIN GENE EXPRESSION BY HUMAN T CELL LEUKEMIA VIRUS TYPE I

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

REGULATION OF LYMPHOTOXIN GENE EXPRESSION BY HUMAN T CELL LEUKEMIA VIRUS TYPE I

Diss Abstr Int [B]; 52(2):648 1991. Unique Identifier : AIDSLINE ICDB/92677944
Paul NL; Yale Univ.

Abstract: HTLV-I infected CD4+ T cell lines (MT-2 and HUT-102) constitutively express high levels of LT mRNA and protein. The nonproductively transformed C81-66-45 cell line, which expresses the HTLV-I transactivator tax-I, also constitutively produces LT. To understand regulation of LT transcription by HTLV-I, a series of deletions of the LT promoter were tested for their ability to drive the chloramphenicol acetyl transferase (CAT) reporter gene in H9, C81-66-45, and MT-2 cells. The smallest fragment of the LT promoter that was able to drive CAT activity (-140/+77 LT) contains a site that is similar to the immunoglobulin kappa chain NF-kappaB binding site. As the HTLV-I tax gene has been shown to activate the nuclear form of NF-kappaB, this suggested a possible means of HTLV-I activation of LT production. Results from electrophoretic mobility shift studies with the human LT kappaB-like site and nuclear extracts from HTLV-I infected and noninfected human T cell lines indicate that the LT site forms a specific complex. Mutation of the kappaB site in the context of the LT promoter (-293/+77) caused a decrease in CAT activity in HTLV-I infected and noninfected human T cell lines. Transfection of H9 cells with tax-I or treatment with anti-CD3 antibody led to increased NF-kappaB activity but had no effect on the activity of cotransfected LT-CAT constructs. Anti-CD3 antibody increased levels of endogenous LT in H9 cells but tax-I had no detectable effect on levels of endogenous LT. Thus, the LT kappaB site is necessary for basal promoter activity but NF-kappaB activation is not sufficient for LT expression. HTLV-I activation of LT is mediated by tax-I only in certain cellular environments. The inappropriate expression of LT as a consequence of HTLV-I infection may explain the pathology associated with HTLV-I infection, including the hypercalcemia that is prevalent in adult T cell leukemia. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD91-21113).

Keywords: Antigens, Differentiation, T-Lymphocyte/IMMUNOLOGY Cell Line Chloramphenicol Acetyltransferase/ANALYSIS *Gene Expression Regulation, Viral Gene Products, tax/PHYSIOLOGY Human HTLV-I Infections/*GENETICS Lymphotoxin/BIOSYNTHESIS/*GENETICS Promoter Regions (Genetics) Receptors, Antigen, T-Cell/IMMUNOLOGY THESIS

920130
M9210767

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