LYMPHOKINE MRNA BINDING PROTEINS

转录后机制在调节T细胞中发挥重要作用 活化和淋巴因子产生。细胞因子、原癌基因和 转录因子基因编码的mRNA通常通过以下方式区分： 细胞质不稳定性（半衰期<30分钟）。许多不稳定的 mRNA中包含特定序列（AUUUA）的重复 3'UTR。已经显示了该AUUUA序列（ARE）的重复 能够赋予mRNA不稳定性以及调节其 能力被翻译。在研究了IRE-BP/乌头酸酶在 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- 与重复的AUUUA序列结合的作用因子。在这 建议，我们计划识别，功能特征，并克隆 反式作用蛋白（富含AU序列结合蛋白; AUBP） 结合AUUUA多聚体并调节淋巴因子mRNA周转， 翻译.通过鉴定存在于细胞中的四种细胞质AUBP T淋巴细胞作为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， 现在可以研究它们的翻译后调节。给定 转录后机制在调控中的重要性 淋巴因子基因表达，这些研究有直接的相关性 我们对T细胞活化和分化的理解。 定义与淋巴因子mRNA稳定性相关的AUBP， 营业额不仅可以使人们深入了解调节机制， 它们的表达，而且还阐明了正常的生理 通过其发生T细胞失活的机制。因此，在本发明中， 表征AUBP功能可能在其中 存在过度的免疫反应性（自身免疫性疾病、变态反应）。 从这些研究中得出的见解将有广泛的应用 超越免疫生物学。AUBP的表征，其调节，以及 它们的功能对于理解 调节细胞生长和分化的途径， 真核细胞大量数据表明， 肿瘤发生的一个重要组成部分是无序的后， 转录调控，导致增强的表达， 原癌基因或生长因子。根据我们对hnRNP A1的鉴定 作为一名AUBP， Friend鼠红白血病病毒经常与 逆转录病毒整合和hnRNPA 1沉默。这些数据 提供相关证据表明，AUBP，特别是hnRNP A1，可能是 在调节细胞生长中很重要，因此是 肿瘤性转化因此，了解这些角色 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 临床病症表现为它们的失调。

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.