| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia (ATL), and the distinct pathogenecity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. We found two crucial differences between Tax1 and Tax2. 1, Tax1 but not Tax2 interacts with NF-kB2/p100, and activates it by inducing the cleavage of p100 into the active transcription factor, p52. The RNA interference method demonstrated that NF-kB2/p100 is required for the transformation induced by Tax1 but not Tax2, as determined by their ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2) dependent growth into independent growth. While Tax2 showed a reduced transforming activity relative to Tax1, a Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 showed an equivalent transforming activity to Tax1 in CTLL-2 expressing an inducer of p52 processing (an active form of NF-κB inducing kinase). These results reveal the activation of NF-κB2/p100 to play a crucial role in the Tax1-mediated transformation of T-cells, and NF-κB2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2. 2, Tax2 stimulated gene expression of interleukin (IL)-2 through the nuclear factor of activated T cells (NFAT). However, the activity of HTLV-1 Tax1 was minimal in this system. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells.
Our results suggest that the distinct transformation mechanism of Tax1 relative to Tax2 play crucial role in HTLV-1 specific leukemogenesis.
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