MESSENGER RNA DECAY OF IMMEDIATE EARLY GENES

描述：拟议研究的长期目标是 阐明管理差异性和选择性的基本原则 哺乳动物细胞中信使RNA（mRNA）降解。 什么顺式作用 mRNA中的元素决定了它的半衰期 哪些监管因素和 酶参与降解mRNA？ mRNA的稳定性如何 监管？ 为实现这一目标，本建议侧重于 一组富Au元素（战神）发挥作用的分子机制 来介导mRNA的快速降解。 战神存在于3'端未翻译的 许多高度不稳定的立即早期基因mRNA的区域， 癌蛋白、核转录因子和细胞因子。 它们代表 最常见的RNA稳定性决定子， 哺乳动物细胞 提出了五个具体目标。 第一个目标是 识别和表征战神的关键序列特征，并确定 它们在指定战神的不稳定功能中的作用。 这将 涉及创建不同战神的定义突变，并通过在 体内基因转染实验。 第二个目的是调查 3' poly（A）尾的作用和指示性的溶核事件 ARE介导的衰变途径。 第三个目标是确定和 表征参与ARE介导的mRNA的细胞因子 降解 第四个目的是研究 实现了ARE功能的差分调节。 最终目标是 研究翻译与ARE指导的关系 mRNA衰变。 拟议的研究可能会增加对一个基本问题的认识， 基因表达的一个方面，目前还知之甚少。 因为 几种含ARE的原癌基因mRNA的显著不稳定性有助于 通过这些基因，调节蛋白， 参与这些原癌基因mRNA快速转换的基因本身可能是 抑癌基因的潜在产物。 因此，知识 从拟议的研究中学到的东西最终可能对 了解肿瘤发生的分子机制。

DESCRIPTION: The long-range objective of the proposed research is to elucidate the fundamental principles that govern differential and selective messenger RNA (mRNA) degradation in mammalian cells. What cis-acting elements in an mRNA determine its half-life? What regulatory factors and enzymes are involved in degrading mRNAs? How are mRNA stabilities regulated? Towards achieving that goal, this proposal focuses on the molecular mechanisms by which a group of AU-rich elements (AREs) functions to mediate rapid mRNA degradation. AREs are found in the 3' untranslated region of many highly unstable immediate-early-gene mRNAs that code for oncoproteins, nuclear transcription factors and cytokines. They represent the most common RNA stability determinant among those characterized in mammalian cells. Five specific aims are proposed. The first aim is to identify and characterize the key sequence features of AREs and determine their roles in specifying the destabilizing function of AREs. This will involve creating defined mutations of different AREs and testing them by in vivo gene transfection experiments. The second aim is to investigate the role of the 3' poly(A) tail and the nucleolytic events that are indicative of the ARE-mediated decay pathways. The third aim is to identify and characterize the cellular factors that participate in the ARE-mediated mRNA degradation. The fourth aim is to investigate the mechanisms by which differential regulation of the ARE function is achieved. The final aim is to study the relationship between translation and the ARE-directed mRNAdecay. The proposed studies may enhance the knowledge of a fundamental aspect of gene expression that presently is poorly understood. Because the marked instability of several ARE-containing proto-oncogene mRNAs helps to prevent oncogenic transformation by these genes, the regulatory proteins involved in rapid turnover of these proto-oncogene mRNAs may themselves be potential products of cancer suppressor genes. Therefore, the knowledge learned from the proposed research may ultimately be of value to understanding molecular mechanisms of tumorigenesis.