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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

基本信息

批准号：
8585035
负责人：
Isabelle Michele Lemasson
金额：
$ 25.04万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8585035
关键词：
Acetyltransferase Address Adult T-Cell Leukemia/Lymphoma 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 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

项目摘要

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.

项目总结。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，各种临床疾病的病原体，包括成人T细胞白血病(ATL)，以及成熟活化T细胞的侵袭性且常常是致命的恶性肿瘤。ATL通常在以下情况下被诊断为几十年的感染，表明长时间的病毒潜伏期导致了这种疾病的发展。HTLV-1碱性亮氨酸拉链因子(HBZ)被认为在病毒潜伏期和T细胞增殖。这种蛋白质定位在细胞核内，携带着一种基本的亮氨酸拉链(BZIP)结构域，通过与适当的蛋白质相互作用促进蛋白质二聚其他蛋白质中的亮氨酸拉链。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与DNA结合，这一效果与 HBZ bZIP域。我们发现HBZ还直接结合到细胞辅活化子p300和 CBP，它是通过病毒蛋白的bZIP结构域以外的区域介导的。在…的背景下对于HTLV-1启动子，我们发现HBZ与CREB和p300/CBP结合是必不可少的。实现对转录的完全抑制。因为HBZ基因是在负链上唯一编码的前病毒的3‘端，它的表达不受这种和其他抑制机制的影响靶向5‘LTR(正常的病毒启动子)。很可能HBZ与细胞内bZIP的结合因子和p300/CBP是其解除许多细胞基因表达调控能力的基础。为了获得深入了解HBZ影响转录的机制，我们已经评估了它的相互作用我们已经确定了它所针对的基因。我们已经获得了 HBZ与ATF/CREB因子形成的复合体在结构上不同于与AP-1因子形成复合体。此外，我们发现HBZ直接针对多个域 P300/CBP，包括KIX、ZZ和TAZ2结构域。在本提案中，我们将解决功能这些相互作用的后果。在目标1中，我们建议剖析HBZ和HBZ之间的相互作用 P300/CBP，并确定这种相互作用的下游影响，包括与特定细胞蛋白相互作用和/或乙酰化的辅助激活剂。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的解除调控。我们将测试是否有异常表达 HTLV-1感染的某些生物学方面可能与发育有关的特定基因构成了基础或ATL的临床表现。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain.

HTLV-1 bZIP 因子通过其激活域激活参与骨吸收的蛋白质 Dkk1 的表达。

DOI：
10.1186/1742-4690-7-61
发表时间：
2010
期刊：
Retrovirology
影响因子：
3.3
作者：
Polakowski,Nicholas;Gregory,Heather;Mesnard,Jean-Michel;Lemasson,Isabelle
通讯作者：
Lemasson,Isabelle

Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1.

DOI：
10.18632/oncotarget.6424
发表时间：
2016-01-12
期刊：
Oncotarget
影响因子：
0
作者：
Wright DG;Marchal C;Hoang K;Ankney JA;Nguyen ST;Rushing AW;Polakowski N;Miotto B;Lemasson I
通讯作者：
Lemasson I

The splice 1 variant of HTLV-1 bZIP factor stabilizes c-Jun.