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KDR/VEGFR2 regulation of HTLV-1 oncogenesis and viral gene expression

KDR/VEGFR2 对 HTLV-1 肿瘤发生和病毒基因表达的调节

基本信息

批准号：
10610829
负责人：
EDWARD W HARHAJ
金额：
$ 20.3万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-18 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610829
关键词：
Adult T-Cell Leukemia/Lymphoma American Antiviral Agents Apoptosis Apoptotic Automobile Driving Biological Assay CREB1 gene Cell Cycle Cell Death Induction Cell Line Cell Survival Cells Chronic Clinic Clinical Clone Cells Complex Critical Pathways Cycloheximide Data Deltaretrovirus Development Disease EP300 gene Etiology Family Foundations Gene Expression Genes Guide RNA Heat-Shock Proteins 90 Human T-lymphotropic virus 1 Immune response Individual Infection Inflammatory Integration Host Factors Investigation KDR gene Knock-out Ligands Link Long Terminal Repeats Lymphoma cell MAP Kinase Signaling Pathways MAPKinase Signaling Pathway Malignant Neoplasms Mediating Modeling Molecular Chaperones Mutation NF-kappa B NF-kappaB-inducing kinase NFKB Activation Pathway Neoplasms North America Oncogenes Oncogenic Oncoproteins Pathogenesis Patients Persons Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Proliferating Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-akt Proviruses Receptor Protein-Tyrosine Kinases Regulation Retroviridae Role Signal Pathway Signal Transduction Solid Neoplasm Spinal Cord Diseases T-Cell Transformation T-Lymphocyte Taxes Testing Tropical Spastic Paraparesis Ubiquitination Vaccines Vascular Endothelial Growth Factors Viral Viral Genes Virus Replication antiviral immunity cell motility cohort disorder risk gain of function genetic regulatory protein human migration inhibitor insight knock-down lentiviral-mediated loss of function migration neoplastic cell novel strategies novel therapeutic intervention receptor recruit risk mitigation small hairpin RNA small molecule small molecule inhibitor tax Gene Products transcription factor tumorigenesis validation studies

项目摘要

The retrovirus human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm that occurs in ~5% of infected individuals after a long latent period. HTLV-1 infection is also associated with a host of inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax is a multifunctional trans-activating protein and key player in pathogenesis. Tax is required for viral gene expression by coordinating the recruitment of the CREB transcription factor and CBP/p300 co-activators to the 5’ viral long terminal repeat (LTR). Tax is also a potent oncogene and induces the persistent activation of the NF- kB pathway to drive the survival, expansion and persistence of HTLV-1-infected T cell clones. Emerging studies have revealed that the expression of HTLV-1 genes is highly dynamic, with prolonged periods of latency to evade antiviral immune responses. However, little is known about host proteins that regulate Tax expression or protein stability which may impact on viral gene expression, host antiviral immunity and the survival of HTLV-1-infected T cells. Furthermore, there is an urgent and unmet clinical need for novel therapeutic approaches for ATLL, a highly aggressive and lethal disease. We have conducted a kinome-wide shRNA screen to identify host factors important for the survival of an HTLV-1- transformed T cell line. The top hit in the screen was the tyrosine kinase receptor KDR/VEGFR2, which we have validated as a critical survival factor in a subset of HTLV-1-transformed T cell lines. Inhibition of KDR with shRNA or a small molecule inhibitor induced cell death selectively in KDR+ HTLV-1-transformed T cells. Furthermore, inhibition of KDR blunted the chronic activation of NF-kB and triggered the degradation of the Tax protein. In this exploratory application, we will investigate the mechanisms by which KDR signaling regulates Tax stability, as well as the role of KDR in the activation of oncogenic signaling pathways, cell survival and migration of HTLV-1- transformed T cells. The central hypothesis driving these investigations is that KDR activates oncogenic signaling pathways in HTLV-1-infected T cells that promote cell survival and the stability of the Tax protein. We will test this hypothesis experimentally with the following Specific Aims: (1) determine the oncogenic role of VEGFR2/KDR in HTLV-1-transformed T cells, and (2) determine how KDR signaling regulates Tax protein stability and viral gene expression. Completion of the proposed studies will provide new insight into the complex regulation of the HTLV-1 Tax oncoprotein and viral gene expression and may lead to new strategies to curtail the proviral load in HTLV-1-infected individuals.

逆转录病毒人类T细胞白血病病毒1型（HTLV-1）是成人T细胞白血病/淋巴瘤（ATLL）的病原体，ATLL是一种侵袭性肿瘤，在长潜伏期后约5%的感染个体中发生。HTLV-1感染还与许多炎性疾病相关，包括HTLV-1相关的脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）。HTLV-1 Tax是一种多功能反式激活蛋白，在发病机制中发挥关键作用。Tax通过协调CREB转录因子和CBP/p300共激活因子向5'病毒长末端重复序列（LTR）的募集而为病毒基因表达所需。Tax也是一种有效的致癌基因，并诱导NF-κ B途径的持续激活，以驱动HTLV-1感染的T细胞克隆的存活、扩增和持续。新的研究表明，HTLV-1基因的表达是高度动态的，具有延长的潜伏期以逃避抗病毒免疫应答。然而，对调节Tax表达或蛋白质稳定性的宿主蛋白知之甚少，这些蛋白质可能影响病毒基因表达、宿主抗病毒免疫和HTLV-1感染的T细胞的存活。此外，对于ATLL（一种高度侵袭性和致死性疾病）的新型治疗方法存在迫切且未满足的临床需求。我们已经进行了一个激酶组范围的shRNA筛选，以确定对HTLV-1转化的T细胞系的存活重要的宿主因子。在筛选中最受欢迎的是酪氨酸激酶受体KDR/VEGFR 2，我们已经证实它是HTLV-1转化T细胞系亚群中的关键存活因子。用shRNA或小分子抑制剂抑制KDR选择性地诱导KDR+ HTLV-1转化的T细胞中的细胞死亡。此外，KDR的抑制减弱了NF-kB的慢性激活，并引发了Tax蛋白的降解。在这一探索性应用中，我们将研究KDR信号调节Tax稳定性的机制，以及KDR在致癌信号通路激活、细胞存活和HTLV-1转化T细胞迁移中的作用。驱动这些研究的中心假设是，KDR激活HTLV-1感染的T细胞中的致癌信号通路，促进细胞存活和Tax蛋白的稳定性。我们将通过以下具体目的实验检验这一假设：（1）确定VEGFR 2/KDR在HTLV-1转化的T细胞中的致癌作用，以及（2）确定KDR信号传导如何调节Tax蛋白稳定性和病毒基因表达。完成拟议的研究将为HTLV-1 Tax癌蛋白和病毒基因表达的复杂调控提供新的见解，并可能导致新的策略来减少HTLV-1感染个体的前病毒载量。