Polyadenylation Factors in B-Cells, Lymphoma & Myeloma

B 细胞中的多聚腺苷酸化因子，淋巴瘤

• 批准号: 6699947
• 负责人: Christine Ann Milcarek
• 金额: $ 26.02万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6699947
• 关键词: Polyadenylation; Factors; Cells; Lymphoma; Myeloma

DESCRIPTION (provided by the applicant): The mRNA 3'-end processing reaction has been shown to play an important role in modulating Ig heavy chain poly(A) site use in B-cell development. This proposal focuses on defining the mechanisms of action of hnRNPF and H/H', auxiliary polyadenylation factors, and how they operate to influence poly(A) site choice during the induction of myeloma/plasma and lymphoma/memory B cells. We propose the following: Aim 1. To define the role of hnRNP F in binding RNA and blocking 3' end processing in cells. A. We will test the hypothesis that specific domains of hnRNP F are responsible for its RNA binding and inhibition of 3' end processing. B. We will test the hypothesis that the differences between hnRNP F and the closely related proteins hnRNP H/H', in the carboxyl-terminal region and between RNA binding domains 2 and 3, are responsible for the differing biological effects of these molecules on 3' processing. C. We will test the hypothesis that specific phosphorylation of CTD will enhance the competition between hnRNP F and CstF-64. AIM 2. We will test the hypothesis that differential loading of 3'-end processing factors occurs both along the Ig heavy chain gene and during different stages of B-cell development. AIM 3. We will test the hypothesis that over-expression of hnRNP F in authentic plasma cells will suppressIg heavy chain secretion by reducing the amount of secretory specific mRNA. AIM 4. We hypothesize that the increased expression of PC4 we have seen in plasma cells influences 3'-endformation by interacting directly with CstF-64.The experiments described in this proposal attempt to find differences in cells that may serve as markers to identify memory, naive, and plasma B-cells as well as to understand the molecular events that determine how memory an/or B-cells may be activated to differentiate into plasma cells. Understanding plasma cell development is important for vaccine development to eradicate infectious diseases, mediating allergic responses and autoimmune diseases, and limiting tumor growth. Understanding the control of polyadenylation is important for understanding and possibly controlling aspects of cell growth, differentiation and malignancy.

描述（由申请人提供）：mRNA 3'末端加工反应已被证明在调节B细胞发育中Ig重链poly(A)位点的使用中发挥重要作用。该提案的重点是定义 hnRNPF 和 H/H'、辅助聚腺苷酸化因子的作用机制，以及它们在骨髓瘤/血浆和淋巴瘤/记忆 B 细胞诱导过程中如何影响聚腺苷酸位点选择。我们提出以下建议： 目标 1. 明确 hnRNP F 在细胞中结合 RNA 和阻断 3' 末端加工中的作用。 答：我们将检验以下假设：hnRNP F 的特定结构域负责其 RNA 结合和 3' 末端加工抑制。 B. 我们将检验以下假设：hnRNP F 和密切相关的蛋白质 hnRNP H/H' 在羧基末端区域以及 RNA 结合域 2 和 3 之间的差异是导致这些分子对3'处理。 C. 我们将检验 CTD 的特异性磷酸化将增强 hnRNP F 和 CstF-64 之间的竞争的假设。 目标 2. 我们将检验以下假设：3' 端加工因子的差异加载同时发生在 Ig 重链基因上和 B 细胞发育的不同阶段。 目的 3. 我们将检验以下假设：在真正的浆细胞中过度表达 hnRNP F 将通过减少分泌特异性 mRNA 的量来抑制 Ig 重链分泌。 目的 4. 我们假设我们在浆细胞中看到的 PC4 表达增加通过与 CstF-64 直接相互作用影响 3' 末端形成。本提案中描述的实验试图找到细胞中的差异，这些差异可以作为识别记忆的标记、幼稚 B 细胞和浆细胞，以及了解决定记忆和/或 B 细胞如何被激活以分化为浆细胞的分子事件。了解浆细胞的发育对于开发疫苗以消除传染病、介导过敏反应和自身免疫性疾病以及限制肿瘤生长非常重要。 了解多聚腺苷酸化的控制对于理解和可能控制细胞生长、分化和恶性肿瘤的各个方面非常重要。