Myc-directed control of mRNA turnover in lymphopoiesis and lymphomagenesis

Myc 定向控制淋巴细胞生成和淋巴瘤发生中的 mRNA 周转

• 批准号: 8446311
• 负责人: John L. Cleveland
• 金额: $ 38.62万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446311
• 关键词: 3' Untranslated Regions; Apoptosis; Apoptotic; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; Binding Proteins; Biology; Cachexia; Cell physiology; Chromosomal Duplication; Chromosomal translocation; Coin; DNA damage checkpoint; Data; Defect; Development; Elements; Family; Family member; Genes; Genetic; Genetic Transcription; Goals; Human; IL7 gene; Indium; Knock-out; Knockout Mice; Lymphoma; Lymphomagenesis; Lymphopoiesis; Maintenance; Malignant Neoplasms; Messenger RNA; Metabolism; Modeling; Mus; Mutation; Neoplasm Metastasis; Oncogene Proteins; Oncogenes; Pathway interactions; Pharmaceutical Preparations; Play; Premalignant; Process; Protein Binding; Regulator Genes; Repression; Research; Role; Signal Pathway; Signal Transduction; TIS11 protein; TNF gene; Testing; Transcript; Transgenic Organisms; Transplantation; Tumor Angiogenesis; Tumor Suppressor Genes; Tumor Suppressor Proteins; Untranslated Regions; c-myc Genes; cell growth; leukemia/lymphoma; malignant state; mouse model; nucleolin; overexpression; programs; protein function; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Activation of Myc family oncogenes, either directly via chromosomal translocations or amplification, or indirectly via mutations in tumor suppressors or mitogenic signaling pathways, is a hallmark of rapidly dividing human leukemia and lymphoma, as well as a cast of other malignancies. Our studies and those of others in the Myc field have shown that the pervasive selection for activating Myc in cancer reflects its normal function as a master transcriptional regulator of genes necessary for cell growth, metabolism and division, as well as responses that appear more germane to the supraphysiological levels of Myc found in tumors, specifically apoptosis, metastasis, and tumor angiogenesis. Our Preliminary Studies have now revealed that Myc controls yet another fundamental cellular process - the turnover of unstable mRNAs harboring AU-rich elements (AREs) in their 3' untranslated regions - and, importantly, they have established that this response is rate-limiting for the development of Myc-induced lymphoma and that it is essential for maintenance of the malignant state. Mechanistically, our data establish that mRNA turnover is controlled by Myc's ability to regulate the transcription of a select cast of genes encoding ARE-binding proteins (AUBPs) that bind to and destabilize or stabilize labile mRNAs harboring AREs. Further, our data indicate that the Myc-to-AUBP response is also manifest during B cell development. Finally, our analyses indicate that this Myc-to-AUBP response is a hallmark of human B cell lymphoma with MYC involvement. In Specific Aim 1 we will test the hypothesis that c-Myc normally controls the transcription of select AUBPs during B cell development and that these AUBPs and their ARE-containing mRNA targets are necessary for B cell development and proliferation. In Specific Aim 2 we will define the mechanism by which Myc-regulated AUBPs and their mRNA targets control tumor progression and the maintenance of the malignant state. We will also test the intriguing hypothesis that Myc-regulated AUBPs themselves can function as tumor suppressors or as oncogenes. We submit the proposed studies will identify new targets that play key roles in lymphopoiesis and that can be exploited for the development of new anti-lymphoma drugs that are likely to have activity against other human tumors having MYC involvement.

描述（由申请人提供）： Myc家族癌基因的激活，无论是直接通过染色体易位或扩增，或间接通过肿瘤抑制因子或促有丝分裂信号传导途径的突变，是快速分裂的人类白血病和淋巴瘤以及其他恶性肿瘤的标志。我们的研究和其他Myc领域的研究表明，在癌症中激活Myc的普遍选择反映了其作为细胞生长，代谢和分裂所需基因的主转录调节因子的正常功能，以及与肿瘤中发现的Myc的超生理水平更密切相关的反应，特别是凋亡，转移和肿瘤血管生成。我们的初步研究现在已经揭示，Myc控制另一个基本的细胞过程-在其3'非翻译区中含有富含AU的元件（战神）的不稳定mRNA的周转-并且，重要的是，他们已经确定这种反应对于Myc诱导的淋巴瘤的发展是限速的，并且对于维持恶性状态是必不可少的。从机制上讲，我们的数据确定，mRNA周转是由Myc的能力，以调节转录的选择演员的基因编码ARE结合蛋白（AUBP），结合和不稳定或稳定不稳定的mRNA窝藏战神。此外，我们的数据表明Myc对AUBP的反应在B细胞发育过程中也很明显。最后，我们的分析表明，这种Myc对AUBP的反应是MYC参与的人B细胞淋巴瘤的标志。在具体目标1中，我们将检验以下假设：c-Myc在B细胞发育过程中正常控制选择的AUBP的转录，并且这些AUBP及其含ARE的mRNA靶标是B细胞发育和增殖所必需的。在具体目标2中，我们将定义Myc调节的AUBP及其mRNA靶点控制肿瘤进展和恶性状态维持的机制。我们还将测试一个有趣的假设，即Myc调控的AUBP本身可以作为肿瘤抑制因子或癌基因发挥作用。我们提交的研究将确定在淋巴细胞生成中发挥关键作用的新靶点，并可用于开发新的抗淋巴瘤药物，这些药物可能对其他涉及MYC的人类肿瘤具有活性。