PROPERTIES OF THE HTLV I TAX PROTEIN

HTLV I Tax 蛋白的特性

• 批准号: 2895927
• 负责人: Richard B Gaynor
• 金额: $ 23.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895927
• 关键词: HeLa cells; cAMP response element binding protein; enzyme mechanism; genetic library; genetic regulation; genetic regulatory element; genetic transcription; human T cell lymphotropic virus type 1; immunoaffinity chromatography; immunoprecipitation; intermolecular interaction; nuclear factor kappa beta; phosphorylation; virus genetics; virus protein; yeast two hybrid system

DESCRIPTION (adapted from applicant's abstract): HTLV-I Tax protein is critical for the activation of gene expression through both the CREB and NF-kB transcriptional pathways and is also responsible for the transformation of T-lymphocytes. Tax activates HTLV-I gene expression through three regulatory elements in the LTR known as the 21 bp repeats that contain binding sites for the ATF/CREB family. However, Tax will not activate gene expression from cellular promoters containing CRE elements, indicating that the overall structure of the 21 bp repeats is critical for its activation. Tax also activates gene expression via NF-kB binding sites and increases the gene expression of specific cellular genes. Dr. Gaynor's studies indicate that direct interactions between CREB and Tax result in the formation of a stable complex on the 21 bp repeats which markedly increases the recruitment of the coactivator CBP. CBP binds to a number of different cellular regulatory proteins including CREB and it is likely involved in bridging factors bound to upstream control elements with components of the basal transcription complex. Recent studies also indicate that CBP can directly interact with NF-kB proteins. Tax activation via NF-kB binding sites is potentially mediated through both direct or indirect interactions of Tax with NF-kB proteins and by Tax activation of cellular kinases that phosphorylate IkB resulting in its degradation and the constitutive nuclear expression of NF-kB. Four specific aims are proposed to extend these studies and to characterize cellular factors that modulate Tax function in an effort to determine its mechanism of action. The aims are: (1) to identify cellular factors that associate with Tax, (2) to determine the function of those factors, (3) to analyze how CBP modulates Tax activation via CREB and NF-kB pathways, and (4) to determine how Tax modulates the activity of kinases that phosphorylate IkB. The overall objective is to increase understanding of the mechanism of Tax transcriptional activation and transformation.

描述(摘自申请者摘要)：HTLV-I Tax蛋白是 对通过CREB和CREB激活基因表达至关重要 核因子-kB的转录途径，也负责 T淋巴细胞的转化。TAX激活HTLV-I基因表达 通过LTR中的三个调控元素，称为21个BP重复 包含ATF/CREB家族的结合位点。然而，税收不会 激活含有Cre元件的细胞启动子的基因表达， 这表明21个碱基重复序列的整体结构对 它的激活。Tax还通过核因子-kB结合位点激活基因表达 并增加特定细胞基因的基因表达。盖纳医生的 研究表明，CREB和税收之间的直接相互作用导致 在21个碱基重复序列上形成稳定的复合体，显著增加 招募共同激活者CBP。CBP绑定到许多不同的 包括CREB在内的细胞调节蛋白，可能参与了 将绑定到上游控制元素的因素与 基本转录复合体。最近的研究还表明，CBP可以 直接与核因子-kB蛋白相互作用。通过核因子-kB结合激活税收 站点可能通过直接或间接的相互作用进行中介 通过税收与核因子-kB蛋白和通过税收激活的细胞激酶， 使IKB磷酸化，导致其降解和构成核 核因子-kB的表达。提出了四个具体目标来扩大这些目标 研究和表征调节税收功能的细胞因子 为确定其作用机制所做的努力。目标是：(1) 确定与税收相关的细胞因素，(2)确定 这些因素的作用，(3)分析CBP是如何调节税收激活的 通过CREB和NF-kB途径，以及(4)确定税收如何调节 使IKB磷酸化的激酶的活性。总体目标是 加深对Tax转录激活机制的理解 和转型。