PROPERTIES OF THE HTLV I TAX PROTEIN

HTLV I Tax 蛋白的特性

• 批准号: 6376398
• 负责人: Noelle Sevilir Williams
• 金额: $ 24.67万
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376398
• 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（根据申请人的摘要改编）：htlv-i税蛋白是 对于通过CREB和CREB激活基因表达至关重要 NF-KB转录途径，也负责 T淋巴细胞的转化。 税收激活HTLV-I基因表达 通过LTR中的三个调节元素，称为21 bp重复 包含ATF/CREB家族的绑定位点。 但是，税不 激活来自含有CRE元件的细胞启动子的基因表达， 表明21 bp重复的整体结构对于 它的激活。 税收还通过NF-KB结合位点激活基因表达 并增加了特定细胞基因的基因表达。 盖诺尔博士 研究表明，Creb与税收之间的直接相互作用导致 在21 bp重复序列上形成稳定的复合物，这显着增加 共激活因子CBP的募集。 CBP与许多不同的不同 细胞调节蛋白在内，包括CREB，它可能参与 与上游控制元素结合的桥接因子与成分 基础转录复合物。 最近的研究还表明CBP可以 直接与NF-KB蛋白相互作用。 通过NF-KB结合激活税收 站点可能通过直接或间接相互作用来介导 用NF-KB蛋白和通过税收激活细胞激酶的税收 磷酸化IKB导致其降解和本构核 NF-KB的表达。 提出了四个具体目标来扩展这些 研究并表征调节税收功能的细胞因素 确定其作用机理的努力。 目的是：（1） 确定与税收相关的细胞因素，（2）确定 这些因素的功能，（3）分析CBP如何调节税收激活 通过CREB和NF-KB途径，（4）确定税收如何调节 磷酸化IKB的激酶的活性。 总体目标是 增加对税收转录激活机制的理解 和转型。

项目成果

Identification and validation of genes involved in the pathogenesis of colorectal cancer using cDNA microarrays and RNA interference.

• 发表时间: 2003-03
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: N. Williams;R. Gaynor;S. Scoggin;U. Verma;T. Gokaslan;C. Simmang;J. Fleming;Denise Tavana;E. Fren

I-kappa B kinases alpha and beta have distinct roles in regulating murine T cell function.

I-kappa B 激酶 α 和 β 在调节小鼠 T 细胞功能中具有不同的作用。

• DOI: 10.4049/jimmunol.168.8.3721
• 发表时间: 2002
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ren,Hong;Schmalstieg,Aurelia;vanOers,NicolaiSC;Gaynor,RichardB
• 通讯作者: Gaynor,RichardB

Sulindac enhances tumor necrosis factor-alpha-mediated apoptosis of lung cancer cell lines by inhibition of nuclear factor-kappaB.

Sulindac 通过抑制核因子-κB 增强肿瘤坏死因子-α 介导的肺癌细胞系凋亡。

• 发表时间: 2002
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research.
• 作者: Berman,KevinS;Verma,UditN;Harburg,Gwyndolen;Minna,JohnD;Cobb,MelanieH;Gaynor,RichardB
• 通讯作者: Gaynor,RichardB