Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Activation of NF-kappa-B by the Epstein-Barr virus latent membrane protein (LMP1).
Diss Abstr Int [B]; 55(6):2076 1994. Unique Identifier : AIDSLINE ICDB/95615342 Chien M; State Univ. of New York at Buffalo
Abstract:
Epstein-Barr virus (EBV) is strongly associated with two human malignant diseases, Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma, and has been shown to be the causative agent of infectious mononucleosis. In vitro, EBV is able to infect and transform human B-lymphocytes into immortalized cell lines. One of the viral gene products believed to have oncogenic potential is the latent membrane protein (LMP1). It was previously shown that LMP1 can transactivate the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1) through induction of NFkappaB activity in nonlymphoid cells (Hammarskjold and Simurda, 1992). In this study we showed that LMP1 was able to efficiently induce NFkappaB activity in human T-lymphoid cells (Jurkat) and monocytic cells (U937). NFkappaB complexes could be detected in the nuclei of transfected Jurkat cells using gel mobility shift assays. Using specific antibodies, we demonstrated that these complexes contained NFkappaB subunits NFkappaB1, NFkappaB2, RelA and c-Rel. Activation of NFkappaB by LMP1 in Jurkat cells was strongly inhibited by an antioxidant, pyrrolidine dithiocarbamate (PDTC), but was unaffected by staurosporine, a potent protein kinase C inhibitor. In contrast, activation of NFkappaB through phorbol ester (PMA) stimulation of these cells was strongly inhibited both by staurosporine and PDTC. We also found that LMP1 was unable to activate NFkappaB in Jurkat cells constitutively expressing the Tax protein of human T cell leukemia virus type I. This result is consistent with the hypothesis that LMP1 and Tax share a common pathway, possibly oxygen radicals, to activate NFkappaB. Experimental results also showed that the NFkappaB complexes induced by LMP1 were able to bind to the NFkappaB consensus sequence in the promoter of the interleukin 2 alpha receptor gene and induce expression from a minimal promoter linked to four tandem copies of this sequence. In addition, we demonstrated that all three (N-, transmembrane, and C-terminal) domains of LMP1 were required for NFkappaB induction in Jurkat cells. Furthermore, our data suggested the existence of a cellular repressor(s) for HIV-1 gene expression that works through NFkappaB and/or SP1 sites of the viral LTR. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-29789)
Keywords: Alkaloids/PHARMACOLOGY Gene Products, tax/METABOLISM Human HIV-1/GENETICS NF-kappa B/*METABOLISM Oncogene Proteins, Viral/*PHARMACOLOGY Promoter Regions (Genetics) Protein Kinase C/ANTAGONISTS & INHIB Pyrrolidines/PHARMACOLOGY Receptors, Interleukin-2/GENETICS T-Lymphocytes/*METABOLISM Thiocarbamates/PHARMACOLOGY Viral Matrix Proteins/*PHARMACOLOGY THESIS 951230
M95C3242
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
