PROPERTIES TO THE HTLV I TAX PROTEIN

描述（改编自申请人的摘要）：HTLV-I Tax蛋白是 对于通过CREB和 NF-kB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中的三个调控元件，即21 bp重复序列， 含有ATF/CREB家族的结合位点。 然而，税收不会 从含有CRE元件的细胞启动子激活基因表达， 这表明21 bp重复序列的整体结构对于 其激活。 Tax还通过NF-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 研究表明，CREB和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， 辅活化剂CBP的募集。 CBP与许多不同的 包括CREB在内的细胞调节蛋白，它可能参与 与上游控制元素绑定的桥接因子， 基础转录复合体 最近的研究还表明，CBP可以 直接与NF-κ B蛋白相互作用。 通过NF-kB绑定激活税务 位点可能通过直接或间接相互作用介导 Tax与NF-κ B蛋白的结合以及Tax激活细胞激酶， 磷酸化IkB，导致其降解， NF-κ B的表达。 提出了四个具体目标，以扩大这些 研究和表征调节Tax功能的细胞因子， 努力确定其作用机制。 目的是：（1） 识别与税收相关的细胞因素，（2）确定 分析CBP如何调节税收激活 通过CREB和NF-kB途径，以及（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Tax转录激活机制的理解 和转变。

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.