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

HTLV-I Tax诱导的NF-kB在ICN1激活和vir永生化中的作用

• 批准号: 8606171
• 负责人: CHRISTOPHE P NICOT
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-17 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606171
• 关键词: Acute leukemia; Adult T-Cell Leukemia/Lymphoma; Apoptosis; Applications Grants; CD4 Positive T Lymphocytes; Cells; Chromosomal translocation; Clonal Expansion; Cutaneous; Cyclin E; Data; Disease; Dominant-Negative Mutation; FBXW7 gene; Gene Targeting; Genes; Genetic Transcription; Growth; Human; Human T-lymphotropic virus 1; In Vitro; Infection; Inhibition of Apoptosis; Interruption; JUN gene; Laboratories; Maintenance; Malignant Neoplasms; Mean Survival Times; Mediating; Molecular; NF-kappa B; Oncogene Proteins; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Play; Process; Publishing; Radiation therapy; Regimen; Regulatory Pathway; Retroviridae; Role; Signal Transduction; T-Cell Leukemia; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; Taxes; Ubiquitin; Viral; Virus; Virus Diseases; c-myc Genes; cell growth; cell transformation; chemotherapy; in vivo; leukemia; leukemia/lymphoma; lyt-10 protein; mouse model; mutant; neoplastic cell; notch protein; novel; prevent; public health relevance; research study; tax Gene Products; therapeutic target; tumor growth

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.

描述（由申请人提供）：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，这是一种侵袭性致命疾病，其特征是病毒感染的 CD4+T 细胞的克隆扩增。据估计，全世界有 20 至 3000 万人感染 HTLV-I。总体而言，接受各种化疗或放疗方案治疗的HTLV-I感染急性白血病患者的生存期有限，中位生存期为8个月。因此，非常需要识别新的潜在治疗靶点。我们之前的研究表明，细胞内激活的 Notch1 (ICN1) 在 HTLV-I 转化的 T 细胞和 HTLV-I 相关的成人 T 细胞白血病中持续激活，并且对于体内小鼠模型中肿瘤细胞的生长至关重要。我们实验室的最新数据表明，病毒 Tax 癌蛋白可减少 ICN1 的降解，从而在 HTLV-I 感染的细胞中产生组成型信号传导。我们进一步发现 Tax 介导的 NF-kappa B2 激活参与组成型 ICN1 信号传导。 “非典型”NF-kB 通路的激活已成为 T 细胞白血病和淋巴瘤的重要通路。 Nfkb2 基因经常参与与人类皮肤 T 细胞淋巴瘤相关的染色体易位。此外，NF-κB 的激活对于 HTLV-I 转化细胞至关重要，抑制该途径可防止体外和体内肿瘤生长。该项目将研究 Viral Tax 用于防止 ICN1 降解并刺激其靶基因表达的分子机制。我们还将研究在 HTLV-I 感染 T 细胞的早期阶段，激活的 Notch 在增殖和抑制细胞凋亡中的作用。