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: 8839667
• 负责人: John L. Cleveland
• 金额: $ 34.96万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 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/8839667
• 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 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; genetic approach; 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，还是通过肿瘤抑制因子或有丝分裂信号通路的突变间接激活，是快速分裂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 Myc 领域其他人的研究表明，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要转录调节因子的正常功能，以及与肿瘤中发现的 Myc 超生理水平更密切相关的反应，特别是细胞凋亡、转移和肿瘤血管生成。我们的初步研究现已揭示，Myc 控制着另一个基本的细胞过程，即在其 3' 非翻译区含有富含 AU 元件 (ARE) 的不稳定 mRNA 的周转，重要的是，他们已经确定这种反应是 Myc 诱导的淋巴瘤发展的限速因素，并且对于维持恶性状态至关重要。从机制上讲，我们的数据证实，mRNA 周转是由 Myc 调节编码 ARE 结合蛋白 (AUBP) 的选定基因转录的能力控制的，这些蛋白与含有 ARE 的不稳定 mRNA 结合，并使其不稳定或稳定。此外，我们的数据表明 Myc-to-AUBP 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-to-AUBP 反应是 MYC 参与的人类 B 细胞淋巴瘤的标志。在特定目标 1 中，我们将测试以下假设：c-Myc 在 B 细胞发育过程中通常控制选定 AUBP 的转录，并且这些 AUBP 及其包含 ARE 的 mRNA 靶标对于 B 细胞发育和增殖是必需的。在具体目标 2 中，我们将定义 Myc 调节的 AUBP 及其 mRNA 靶标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 调节的 AUBP 本身可以充当肿瘤抑制因子或癌基因。我们提出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。