Lymphotoxin activation by human T-cell leukemia virus type I-infected cell lines: role for NF-kappa B.
Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of biologically active lymphotoxin (LT; tumor necrosis factor-beta) protein and LT mRNA. To understand the regulation of LT transcription by HTLV-I, we analyzed the ability of a series of deletions of the LT promoter to drive the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells. The smallest LT promoter fragment (-140 to +77) that was able to drive CAT activity contained a site that was similar to the immunoglobulin kappa-chain NF-kappa B-binding site. Since the HTLV-I tax gene activates the nuclear form of NF-kappa B, this finding suggested a possible means of HTLV-I activation of LT production. We found that the LT kappa B-like site specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2, C81-66-45, and other activated T cells. Mutation of the LT kappa B site in the context of the LT promoter (-293 to +77) (mutant M1) reduced the ability of the promoter to drive the CAT gene in HTLV-I-infected and noninfected human T-cell lines. These data suggest a general role for NF-kappa B activation in the induction of LT gene transcription. Activation of LT in HTLV-I-infected cells may explain the pathology associated with HTLV-I infection, including the hypercalcemia that is prevalent in adult T-cell leukemia.
Paul
N L
NL
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510.
Lenardo
M J
MJ
Novak
K D
KD
Sarr
T
T
Tang
W L
WL
Ruddle
N H
NH
D001483:Base Sequence; D015152:Blotting, Northern; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology*; D002460:Cell Line; D006800:Deltaretrovirus Infections / Q000503:physiopathology*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008233:Lymphotoxin-alpha / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid
D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D009687:Nuclear Proteins; D012333:RNA, Messenger