Lymphoma development in the elderly: Perturbed posttranscriptional regulation

 描述(由申请人提供)： 项目概述/摘要本项目的目标是了解与衰老相关的人类弥漫性大B细胞淋巴瘤(DLBCL)发病率增加的机制基础。几十年来，众所周知，衰老小鼠经常患上淋巴瘤，在小鼠模型中的工作已经发现了与年龄相关的DNA损伤反应(DDR)的减少。ATM基因是DNA损伤信号通路的主要调节者，与共济失调-毛细血管扩张症(AT)有关，对维持基因组的完整性是必不可少的。莱文的研究小组证明，随着年龄的增长，小鼠ATM激酶的功能显著下降。与临床相关的是，老年人的外周血淋巴细胞在暴露于基因毒性应激后也表现出减弱的反应。有趣的是，相当大比例的DLBCL表现出致癌的microRNA-421水平升高，它下调ATM蛋白的水平。基因毒性应激暴露后，基因表达水平受转录和转录后/翻译两种事件的调控。RNA结合蛋白(RBP)和microRNAs是基因表达的主要转录后/翻译调控因子。这种对mRNA亚群的同步调节是转录后“RNA操纵子”模型的基础，在该模型中，RBPs共同调节多个mRNAs，从而调节具有相关功能的蛋白质的共同表达。RBP，HUR被认为是编码细胞应激反应中心蛋白的mRNAs的关键转录后调节因子。我们的团队最近发现了那些与HUR差异相关的转录本，包括以ATM/Chk2依赖的方式与癌症相关的多个mRNAs。需要研究的具体假设是，HUR对IR反应的基因转录后调控异常有助于老年人的淋巴肿大。在特定的目标1中，我们将研究人类B细胞淋巴细胞中基因转录后异常调控与衰老之间的联系。在特定的目标2，我们将调查致癌的microRNA-421是否有助于DLBCL的发展。在特定的目标3中，我们将研究衰老小鼠脾淋巴瘤的发展是否与转录后基因调控缺陷有机械联系。我们的建议应该在ATM和HUR在介导致癌和抗凋亡活性方面的转录后作用之间提供功能联系，并验证ATM功能与年龄相关的下降是随着年龄增长而观察到的非霍奇金淋巴瘤(NHL)发病率增加的基础这一范式。

 DESCRIPTION (provided by applicant): Project Summary/Abstract The goals of this project are to understand the mechanistic basis for the increased incidence of diffuse large B cell lymphoma (DLBCL) associated with aging in humans. It has been known for decades that aging mice frequently develop lymphomas and work in mouse models have identified age-associated reduction in the DNA damage response (DDR). The ATM gene, a master regulator of the DNA damage-signaling pathways is responsible for ataxia-telangiectasia (AT), and is essential for maintaining the integrity of the genome. The Levine group demonstrated that the function of ATM kinase declines significantly with age in mice. Of clinical relevance, human peripheral blood lymphocytes from older individuals also demonstrate an attenuated response after exposure to genotoxic stresses. Interestingly, a significant percentage of DLBCL exhibited elevated levels of the oncogenic microRNA-421 which down-regulates levels of ATM protein. The levels of expressed genes are controlled through both transcriptional and post-transcriptional/translational events after genotoxic stress exposure. RNA-binding proteins (RBP) and microRNAs are major posttranscriptional/ translational regulators of gene expression. This synchronized regulation of mRNA subsets is the basis of the post-transcriptional "RNA-operon" model whereby RBPs coregulate multiple mRNAs and thereby regulate the co-expression of proteins with related function. The RBP, HuR is recognized as a key post-transcriptional regulator of mRNAs encoding proteins central to the cellular stress response. Our group recently identified those transcripts differentially associated with HuR, including multiple cancer-related mRNAs in an ATM/Chk2- dependent manner. The specific hypothesis to be investigated is that the aberrant posttranscriptional regulation of genes by HuR in response to IR contributes to lymphomagenesis in the elderly. In Specific Aim 1, we will investigate the linkage between aberrant post-transcriptional regulation of genes and aging in human B- cell lymphocytes. In Specific Aim 2, we will investigate if the oncogenic microRNA-421 contributes to DLBCL development. In Specific Aim 3, we will investigate whether the development of splenic lymphomas in aging mouse are mechanistically linked with defects in post-transcriptional gene regulation. Our proposal should provide a functional link between ATM and HuR's posttranscriptional role in mediating oncogenic, and antiapoptotic activities as well as to validat the paradigm that the age-associated decline in function of ATM underlies the increased incidence of non-Hodgkin's lymphoma (NHL) observed with increasing age.