Leukemia Virus Long Terminal Repeat Activates Nfkappab Pathway by a Tlr3-dependent Mechanism.
From: Cancer Research Center, Boston University School of Medicine, 715 Albany Street, R908, Boston, MA 02118, USA.
Virology
- Publish Date: Feb 2006
- ISSN: 0042-6822
- Volume: 345
- Issue: 2
- Pages: 390-403
- Medium: Print
- Language: English
- Citation (JAMA): Abujamra Ana L, Spanjaard Remco A, Akinsheye Idowu, et al. Leukemia Virus Long Terminal Repeat Activates Nfkappab Pathway by a Tlr3-dependent Mechanism.. Virology Feb 2006;345:390-403
Abstract
The long terminal repeat (LTR) region of leukemia viruses plays a critical role in tissue tropism and pathogenic potential of the viruses. We have previously reported that U3-LTR from Moloney murine and feline leukemia viruses (Mo-MuLV and FeLV) upregulates specific cellular genes in trans in an integration-independent way. The U3-LTR region necessary for this action does not encode a protein but instead makes a specific RNA transcript. Because several cellular genes transactivated by the U3-LTR can also be activated by NFkappaB, and because the antiapoptotic and growth promoting activities of NFkappaB have been implicated in leukemogenesis, we investigated whether FeLV U3-LTR can activate NFkappaB signaling. Here, we demonstrate that FeLV U3-LTR indeed upregulates the NFkappaB signaling pathway via activation of Ras-Raf-IkappaB kinase (IKK) and degradation of IkappaB. LTR-mediated transcriptional activation of genes did not require new protein synthesis suggesting an active role of the LTR transcript in the process. Using Toll-like receptor (TLR) deficient HEK293 cells and PKR(-/-) mouse embryo fibroblasts, we further demonstrate that although dsRNA-activated protein kinase R (PKR) is not necessary, TLR3 is required for the activation of NFkappaB by the LTR. Our study thus demonstrates involvement of a TLR3-dependent but PKR-independent dsRNA-mediated signaling pathway for NFkappaB activation and thus provides a new mechanistic explanation of LTR-mediated cellular gene transactivation.
Mesh Headings (Keywords): 3T3 Cells, Animals, Cats, Cell Line, Humans, Leukemia Virus, Feline, Mice, Mice, Inbred BALB C, Moloney murine leukemia virus, NF-kappa B, Terminal Repeat Sequences, Toll-Like Receptor 3, Trans-Activation (Genetics), Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 16289658
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