Poster abstracts
Poster number 101 submitted by Jacob Al-Saleem
The Role of Tax-1 and the Alternative NF-kB and Akt Signaling Pathways in HTLV Transformation
Jacob Al-Saleem (Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA), Mathew Cherian (Division of Oncology, Washington University, St Louis, MO, USA), Hicham Baydoun (Division of Oncology, Washington University, St Louis, MO, USA), Mamuka Kvaratskhelia (Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA), Lee Ratner (Division of Oncology, Washington University, St Louis, MO, USA), Patrick L. Green (Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA)
Abstract:
Human T-cell Leukemia Virus Type-1 (HTLV-1) is a complex retrovirus infecting 15-25 million people worldwide, and is the etiological agent of a malignancy of CD4+ T cells termed Adult T-Cell Leukemia. By contrast, HTLV-2 is non-pathogenic in humans. Both HTLV-1 and HTLV-2 express related Tax proteins termed Tax-1 and Tax-2, respectively. Studies have revealed that Tax-1 contains a C-terminal PDZ (post synaptic density protein) domain binding motif (PBM) and a central leucine zipper region (LZR), which are absent in Tax-2. Previous studies indicated that these two domains are important for the ability of Tax-1 to activate alternative the NF-kB signaling pathway. Since Tax-2 is incapable of activating alternative NF-kB signaling we proposed that Tax-1 activation of the alternative NF-kB pathway is important for the HTLV-1 pathogenesis. We set out to identify binding partners of Tax-1 that are important for activation of alternative NF-kB. Using Tax-1 mutants that do not possess the PBM or LZR we identified several potential candidates via a proteomic screen. We plan to utilize siRNA knockdowns to screen these candidates for importance in Tax-1 driven alternative NF-kB activation. During our analyses we found that deletion of the PBM from Tax-1 did not cause a deficiency, but resulted in an enhancement of alternative NF-kB activation. With further analysis, we found that Tax-1 PBM is important for the ability of Tax-1 to activate Akt. Tax-1 diminishes the function of PTEN (Phospatase and Tensin homologue), which inhibits the PI3K-Akt-mTOR pathway. We found that Tax-1, but not PBM deleted Tax-1, competes with PTEN for binding to DLG-1 (Drosophila disk large tumor suppressor), which leads to an increase in Akt activation. These studies suggest that alternative NF-kB and Akt signaling pathways may explain the differences in HTLV-1 and HTLV-2 pathogenesis. Moreover, these findings suggest a new approach to therapeutics for HTLV-1 diseases.
Keywords: HTLV, Akt, NF-kB