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（由申请方提供）：人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，其特征为病毒感染的CD 4 +T细胞的克隆扩增。据估计，全世界有2000万至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感染的急性白血病患者的生存期有限，中位生存期为8个月。因此，非常需要鉴定新的潜在治疗靶点。我们先前的研究表明，细胞内激活的Notch 1（ICN 1）在HTLV-I转化的T细胞和HTLV-I相关的成人T细胞白血病中被组成性激活，并且对于体内小鼠模型中的肿瘤细胞生长至关重要。我们实验室的最新数据表明，病毒Tax癌蛋白减少ICN 1的降解，导致HTLV-I感染细胞中的组成性信号传导。我们进一步发现Tax介导的NF-κ B2活化参与组成性ICN 1信号传导。“非经典”NF-kB途径的激活已经成为T细胞白血病和淋巴瘤中涉及的重要途径。Nfkb 2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-κ B的活化对于HTLV-I转化的细胞是必不可少的，并且抑制该途径可以在体外和体内防止肿瘤生长。该项目将研究病毒Tax用于防止ICN 1降解并刺激其靶基因表达的分子机制。我们还将研究活化的Notch在HTLV-I感染T细胞的早期阶段增殖和抑制凋亡中的作用。