LYMPHOKINE MRNA BINDING PROTEINS

转录后机制在调节T细胞中起主要作用 活化和淋巴因子的产生。细胞因子、原癌基因和 转录因子基因编码的mRNAs通常由 细胞质不稳定(半衰期和30分钟)。其中许多不稳定 MRNAs包含特定序列(AUUUA)的重复 3‘非编码区。已经显示了该AUUUA序列(ARE)的重复 能够赋予信使核糖核酸的不稳定性以及调节其 能够被翻译。在对IRE-BP/乌头酸酶研究的基础上 细胞铁代谢，我们假设转录后 淋巴因子基因表达的调节高度依赖于反式-核糖核酸。 与重复的AUUA序列结合的作用因子。在这 提议，我们计划识别、功能特征和克隆 反式作用蛋白(AU富含序列结合蛋白；AUBP) 与AUUA多聚体结合并调节淋巴因子mRNA的周转 翻译。四种细胞质AUBPs的鉴定 T淋巴细胞如hnRNP A1、hnRNP C、UP-1和甘油醛3- 磷酸脱氢酶，已经取得了相当大的进展， 这使得现在可以研究他们的翻译后监管。vt.给出 转录后机制在调控中的重要性 对于淋巴因子基因的表达，这些研究具有直接的相关性 有助于我们理解T细胞的激活和分化。 确定与淋巴因子基因稳定性相关的AUBP(S) 周转不仅能让人洞察(S)的调节机制 它们的表达，也阐明了正常的生理 T细胞失活的机制(S)。因此， AUBP功能的特征在以下疾病中可能很重要 免疫反应过度(自身免疫性疾病、过敏)。 从这些研究中得出的见解将得到广泛的应用 超越了免疫生物学。AUBP的特征，它们的调节，以及 它们的功能对于理解 调节急性淋巴细胞白血病细胞生长和分化的途径 真核细胞。有大量数据表明， 肿瘤发生的重要组成部分是后遗症 转录调控，导致A基因表达增强 原癌基因或生长因子。鉴于我们对hnRNP A1的识别 作为一名AUBP，了解到这种转变是非常令人兴奋的 Friend鼠红白血病病毒经常与 逆转录病毒整合和hnRNP A1的沉默。这些数据 提供相关证据表明AUBP，特别是hnRNP A1可能是 在调节细胞生长方面很重要，因此是 肿瘤性转化。因此，理解这些因素的作用 淋巴因子基因表达中的反式作用因子将直接 与免疫生物学和生长调节的相关性，以及 临床疾病表现为他们的失调。

Post-transcriptional mechanisms play a major role in regulating T cell activation and lymphokine production. Cytokine, proto-oncogene, and transcription factor genes encode mRNAs frequently distinguished by cytoplasmic lability (half-life<30 minutes). Many of these unstable mRNAs contain reiterations of a specific sequence (AUUUA) in their 3'UTR. Reiterations of this AUUUA sequence (ARE) have been shown capable of conferring instability on mRNA as well as modulating its ability to be translated. Based on the studies of IRE-BP/aconitase in cellular iron metabolism, we hypothesize that posttranscriptional regulation of lymphokine gene expression is highly dependent on trans- acting factors that bind to reiterated AUUUA sequences. In this proposal, we plan to identify, functionally characterize, and clone the trans-acting proteins (AU-rich sequence binding proteins; AUBP) that bind to AUUUA multimers and modulate lymphokine mRNA turnover and translation. With identification of four cytoplasmic AUBPs present in T lymphocytes as hnRNP A1, hnRNP C, UP-1, and glyceraldehyde 3- phosphate dehydrogenase, considerable progress has already been made, that now permits study of their posttranslational regulation. Given the importance of post-transcriptional mechanisms in the regulation of lymphokine gene expression, these studies have immediate relevance to our understanding of T cell activation and differentiation. Defining the AUBP(s) relevant to lymphokine mRNA stability and turnover will not only enable insight into the mechanism(s) regulating their expression, but also elucidate the normal physiologic mechanism(s) through which deactivation of T cells occurs. Thus, characterizing AUBP function may be important in diseases in which excessive immunoreactivity (autoimmune disease, allergy) is present. Insights derived from these studies will have widespread application beyond immunobiology. Characterization of AUBP, their regulation, and their function will have particular relevance to understanding the pathways that regulate cell growth and differentiation of all eukaryotic cells. Considerable data exists to indicate that an important component of tumorigenesis is disordered post- transcriptional regulation, resulting in enhanced expression of a proto-oncogene or growth factor. Given our identification of hnRNP A1 as an AUBP, it was very exciting to learn that transformation by Friend murine erythroleukemia virus is frequently associated with retroviral integration and silencing of the hnRNP A1. These data provide correlative evidence that AUBP, particularly hnRNP A1, may be important in the regulation of cell growth and hence a target in neoplastic transformation. Thus, understanding the role of these trans-acting factors in lymphokine gene expression will have direct relevance to immunobiology and growth regulation, as well as the clinical disorders manifest by their dysregulation.