Role of HTLV-I Tax-induced NF-kB in activation of ICN1 and immortalization of vir

描述(申请人提供)：人类T细胞白血病病毒1型(HTLV-I)是成人T细胞白血病的病原体，成人T细胞白血病是一种侵袭性和致命性疾病，其特征是感染病毒的CD4+T细胞克隆性增殖。据估计，全球有2000万至3000万人感染了HTLV-I。总体而言，接受各种化疗或放射治疗的感染HTLV-I的急性白血病患者的存活率有限，中位存活期为8个月。因此，迫切需要寻找新的潜在治疗靶点。我们先前的研究表明，在HTLV-I转化的T细胞和HTLV-I相关的成人T细胞白血病中，细胞内激活的Notch1(ICN1)是结构性激活的，并且对于体内小鼠模型中的肿瘤细胞生长是必不可少的。我们实验室的最新数据表明，病毒Tax癌蛋白降低了ICN1的降解，导致HTLV-I感染细胞中的结构性信号。我们进一步发现，税收介导的NF-kappa B2激活参与了ICN1的结构性信号转导。“非规范”的核因子-kB途径的激活已成为T细胞白血病和淋巴瘤的重要途径。NFKB2基因经常与人类皮肤T细胞淋巴瘤相关的染色体易位有关。此外，核因子-kappaB的激活对于HTLV-I转化的细胞是必不可少的，抑制该途径可以防止肿瘤在体外和体内的生长。该项目将研究病毒Tax用于防止ICN1降解并刺激其靶基因表达的分子机制。我们还将研究激活的Notch在HTLV-I感染T细胞的早期阶段在增殖和抑制凋亡中的作用。

DESCRIPTION (provided by applicant): Human T-cell Leukemia Virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia, an aggressive and fatal disease characterized by a clonal expansion of virus-infected CD4+T cells. It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. Overall, survival of HTLV-I-infected patients with acute leukemia treated with various chemotherapy or radiotherapy regimens is limited and median survival is 8 months. Consequently, identification of new potential therapeutic targets is greatly needed. Our studies previously demonstrated that intracellular activated Notch1 (ICN1) is constitutively activated in HTLV-I-transformed T-cells and HTLV-I-associated adult T-cell leukemia, and is essential for tumor cell growth in an in vivo mouse model. Recent data from our laboratory suggest that the viral Tax oncoprotein reduces degradation of ICN1, leading to constitutive signaling in HTLV-I-infected cells. We further found that Tax- mediated NF-kappa B2 activation was involved in constitutive ICN1 signaling. Activation of the "non-canonical" NF-kB pathway has emerged as an important pathway involved in T-cell leukemia and lymphomas. The Nfkb2 gene is frequently involved in chromosomal translocations associated with human cutaneous T-cell lymphomas. In addition, activation of NF-kappaB is essential for HTLV-I-transformed cells and inhibition of the pathway prevents tumor growth in vitro and in vivo. This project will investigate the molecular mechanisms used by viral Tax to prevent the degradation of ICN1 and stimulate expression of its target genes. We will also examine the role of activated Notch in proliferation and inhibition of apoptosis in early phases of HTLV-I infection of T-cells.