Regulation of HTLV-1 and cellular gene transcription by the viral protein HBZ

病毒蛋白 HBZ 对 HTLV-1 和细胞基因转录的调节

• 批准号: 8403665
• 负责人: Isabelle Michele Lemasson
• 金额: $ 24.27万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403665
• 关键词: Acetyltransferase; Address; Adult; Affect; Affinity; Binding; Binding Sites; Biological; Biology; Blood; Breast Feeding; CREB1 gene; Cell Nucleus; Child; Clinical; Coitus; Collection; Complex; Consensus; DNA Binding; Data; Development; Diagnosis; Dimerization; Disease; E1A-associated p300 protein; EP300 gene; Family; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic Transcription; Goals; Human T-lymphotropic virus 1; In Vitro; Infection; JUN gene; Leucine Zippers; Life; Malignant Neoplasms; Mediating; Mothers; N-terminal; Neurodegenerative Disorders; Oncogene Deregulation; Play; Process; Proteins; Proviruses; Regulation; Relative (related person); Repression; Research; Retroviridae; Role; T-Cell Leukemia; T-Cell Proliferation; T-Lymphocyte; Testing; Transcription Factor AP-1; Transcription Regulatory Protein; Viral; Viral Proteins; Virus; Virus Latency; activating transcription factor; activating transcription factor 1; activating transcription factor 4; bZIP Domain; base; dimer; gene repression; in vivo; insight; leukemia; member; prevent; promoter; transcription factor; transmission process

PROJECT SUMMARY. Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that is the causative agent of a variety of clinical disorders including adult T-cell leukemia (ATL), an aggressive and often fatal malignancy of mature activated T-cells. ATL is frequently diagnosed after several decades of infection, suggesting that a long period of viral latency contributes to the development of this disease. The HTLV-1 basic leucine zipper factor (HBZ) is believed to play a role in viral latency and T-cell proliferation. This protein is localized in the nucleus and carries a basic leucine zipper (bZIP) domain that promotes protein dimerization through interactions with appropriate leucine zippers in other proteins. Cellular bZIP factors that are bound by HBZ include certain AP-1 transcription factor components (c-Jun, JunB, JunD) and members of the ATF/CREB family (ATF-1, CREB, CREM and CREB-2). Overall, interactions with HBZ are believed to repress transcription by preventing factors from binding the DNA, an effect that is correlated with the atypical basic region in the HBZ bZIP domain. We found that HBZ also binds directly to the cellular coactivators p300 and CBP, which is mediated through regions of the viral protein outside its bZIP domain. In the context of the HTLV-1 promoter, we found that binding of HBZ to both CREB and p300/CBP is essential to achieve full repression of transcription. As the HBZ gene is uniquely encoded on the minus strand at the 3' end of the provirus, its expression is not affected by this and other mechanisms of repression targeting the 5' LTR (the normal viral promoter). It is likely that the binding of HBZ to cellular bZIP factors and p300/CBP underlie its ability to deregulate expression of many cellular genes. To gain insight into the mechanisms by which HBZ affects transcription, we have evaluated its interactions with cellular transcriptional regulators and we have identified genes that it targets. We have obtained evidence that complexes formed between HBZ and ATF/CREB factors are structurally distinct from complexes formed with AP-1 factors. In addition, we found that HBZ directly targets multiple domains of p300/CBP, including the KIX, ZZ and TAZ2 domains. In this proposal we will address the functional consequences of these interactions. In Aim 1, we propose to dissect the interaction between HBZ and p300/CBP, and determine downstream effects of this interaction, including alterations in the abilities of the coactivator to interact with and/or acetylate specific cellular proteins. In Aim 2, we will compare the interaction of HBZ with ATF/CREB and AP-1 proteins. In Aim 3, we will characterize mechanisms of HBZ-mediated deregulation of cellular gene expression. We will test whether abnormal expression of specific genes underlies certain biological aspects of HTLV-1 infection that may relate to development or clinical presentations of ATL.

项目摘要。人类T细胞白血病病毒1型（HTLV-1）是一种复杂的逆转录病毒， 作为多种临床疾病的病原体，包括成人T细胞白血病（ATL）， 成熟活化T细胞的侵袭性且通常致命的恶性肿瘤。ATL通常在 几十年的感染，这表明病毒潜伏期很长， 这种疾病的发展。HTLV-1碱性亮氨酸拉链因子（HBZ）被认为在 在病毒潜伏期和T细胞增殖方面。这种蛋白质定位于细胞核中，并携带一个基本的 亮氨酸拉链（bZIP）结构域，其通过与合适的氨基酸相互作用促进蛋白质二聚化。 其他蛋白质中的亮氨酸拉链。与HBZ结合的细胞bZIP因子包括某些AP-1 转录因子组分（c-Jun，JunB，JunD）和ATF/CREB家族的成员（ATF-1， CREB、CREM和CREB-2）。总体而言，与HBZ的相互作用被认为通过以下方式抑制转录： 阻止因子结合DNA，这种作用与非典型碱性区域相关， HBZ bZIP结构域。我们发现HBZ还直接与细胞辅激活因子p300和p302结合。 CBP，其通过bZIP结构域以外的病毒蛋白区域介导。背景下 HTLV-1启动子，我们发现HBZ与CREB和p300/CBP的结合对于 实现转录的完全抑制。由于HBZ基因在负链上唯一编码， 前病毒的3'端，其表达不受此抑制机制和其他抑制机制的影响 靶向5' LTR（正常病毒启动子）。很可能HBZ与细胞bZIP的结合 因子和p300/CBP是其解除许多细胞基因表达调节的能力的基础。获得 为了深入了解HBZ影响转录的机制，我们评估了其相互作用 与细胞转录调节因子结合，我们已经确定了它的目标基因。我们所获得 有证据表明，HBZ和ATF/CREB因子之间形成的复合物在结构上不同于 与AP-1因子形成复合物。此外，我们发现HBZ直接靶向多个结构域 p300/CBP，包括KIX，ZZ和TAZ 2结构域。在本提案中，我们将讨论 这些互动的后果。在目标1中，我们建议剖析HBZ与 p300/CBP，并确定这种相互作用的下游效应，包括改变的能力， 所述共活化剂与特异性细胞蛋白相互作用和/或使特异性细胞蛋白乙酰化。在目标2中，我们将比较 HBZ与ATF/CREB和AP-1蛋白的相互作用。在目标3中，我们将描述 HBZ介导的细胞基因表达失调。我们将检测是否有异常表达的 HTLV-1感染的某些生物学方面可能与发育有关， 或ATL的临床表现。