Myc-directed control of mRNA turnover in lymphopoiesis and lymphomagenesis

描述（由申请人提供）：Myc家族癌基因的激活，直接通过染色体易位或扩增，或间接通过肿瘤抑制因子或有丝分裂信号通路的突变，是快速分裂的人类白血病和淋巴瘤以及许多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，Myc在癌症中普遍存在的激活选择反映了它作为细胞生长、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Myc的超生理水平（特别是凋亡、转移和肿瘤血管生成）更为相关的反应。我们的初步研究现在已经揭示了Myc控制着另一个基本的细胞过程——在其3'非翻译区携带富au元素（AREs）的不稳定mrna的周转——重要的是，他们已经确定了这种反应对Myc诱导的淋巴瘤的发展是限速的，并且它是维持恶性状态所必需的。从机制上说，我们的数据表明mRNA的转换是由Myc调节一系列编码ARE-binding蛋白（aubp）的基因的转录的能力控制的，这些基因结合并破坏或稳定含有AREs的不稳定mRNA。此外，我们的数据表明，Myc-to-AUBP反应也在B细胞发育过程中表现出来。最后，我们的分析表明，MYC对aubp的反应是MYC参与的人B细胞淋巴瘤的一个标志。在Specific Aim 1中，我们将验证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及其含are的mRNA靶点是B细胞发育和增殖所必需的假设。在Specific Aim 2中，我们将定义myc调控的aubp及其mRNA靶点控制肿瘤进展和恶性状态维持的机制。我们还将验证一个有趣的假设，即myc调节的aubp本身可以作为肿瘤抑制因子或癌基因。我们提交的拟议研究将确定在淋巴生成中起关键作用的新靶点，并可用于开发新的抗淋巴瘤药物，这些药物可能对其他与MYC有关的人类肿瘤具有活性。

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.