Role of the UPR in myc-induced tumorigenesis

未折叠蛋白反应（UPR）是一种细胞内稳态程序，由过量的 内质网（ER）腔中未折叠/错误折叠的客户蛋白，主要是 细胞保护作用我们先前的研究表明，肿瘤细胞在缺氧和营养缺乏的情况下存活， 应激依赖于ER驻留蛋白和UPR效应子PERK。除了肿瘤 在微环境中，癌基因也已知激活细胞应激反应，包括代谢性应激反应。 应激、凋亡和衰老。MYC是染色体易位或基因扩增的靶点 在许多人类癌症的发展过程中。c-Myc的表达与 上调总细胞蛋白质含量和蛋白质合成速率。这一发现提高了 c-Myc转化的细胞经历高于正常水平的ER应激的可能性。初步 研究中，我们使用了多种受调控的c-Myc激活的遗传模型，以证明Myc 激活UPR的PERK/eIF 2a/Atf 4臂。UPR的激活通过以下途径导致细胞存活增加： 诱导细胞保护性自噬和减少ER释放Ca^*。PERK消融 显著降低Myc诱导的裸鼠自噬、细胞转化和肿瘤形成。 来自E β 1-Myc小鼠和人淋巴瘤的样品显示较高水平的UPR活化， 与相应的正常组织相比。我们认为细胞中蛋白质负荷的增加 过表达c-Myc导致ER应激和UPR的激活，UPR调节ER应激， 促进转化和肿瘤生长。这一假设将在四个具体目标中得到检验： 我们将确定eIF 2a磷酸化、ATF 4和Chop诱导、Nrf 2激活 和miRNA 211在c-Myc诱导的转化中的作用。在具体目标2中，我们将阐明 UPR激活在致癌转化中提供的细胞保护机制， Myc在特定目标3下，我们将研究c-Myc过表达对细胞凋亡的影响。 另外两个主要的普遍定期审议途径。在具体目标4中，我们将确定PERK激活在c-Myc 使用转基因小鼠模型诱导淋巴瘤发生。成功完成这些研究 将首次建立Myc上调作为UPR的细胞自主激活剂， 揭示了抑制Myc依赖性肿瘤发生的新靶点。 相关性（参见说明）： 主要致癌基因c-Myc在恶性肿瘤中被激活，包括淋巴瘤、结肠直肠癌和结肠癌。 神经母细胞瘤未折叠蛋白质反应（Unfolded Protein Response，UPR）越来越被认为是一种机制 肿瘤抗应激和促肿瘤发生的作用。我们的初步发现表明了一个新颖的角色 UPR激活作为c-Myc致肿瘤作用的增强剂。我们建议的研究将调查 Myc在细胞系、动物肿瘤模型和人类样品中激活UPR的机制， 可能导致开发靶向Myc依赖性恶性肿瘤的新疗法。

The Unfolded Protein Response (UPR) is a cellular homeostatic program initiated by an excess of unfolded/misfolded client proteins in the Endoplasmic Reticulum (ER) lumen, with primarily a cytoprotective effect. We previously showed that tumor cell survival under hypoxic and nutrient deprivation stress is dependent on the ER resident protein and UPR effector PERK. In addition to the tumor microenvironment, oncogenes are also known to activate cellular stress responses, including metabolic stress, apoptosis, and senescence. MYC is the target of chromosomal translocation or gene amplification during the development of many human cancers. c-Myc expression has been associated with robust upregulation of both total cellular protein content and rates of protein synthesis. This finding raises the possibility that c-Myc-transformed cells experience a higher than normal level of ER stress. In preliminary studies, we have used multiple genetic models of regulated c-Myc activation, to demonstrate that Myc activates the PERK/elF2a/Atf4 arm of the UPR. Activation of the UPR leads to increased cell survival via the induction of cytoprotective autophagy and reduced release of Ca^* from the ER. PERK ablation significantly reduced Myc-induced autophagy, cell transformation and tumor formation in nude mice. Samples from E)j,-Myc mice and human lymphomas demonstrate higher levels of UPR activation, compared to corresponding normal tissues. We hvpothesize that the increase in protein burden in cells overexpressing c-Myc results in ER stress and activation of the UPR which tempers ER stress and facilitates transformation and tumor growth. This hypothesis will be tested in four specific aims: In Aim 1, we will determine the requirement for elF2a phosphorylation, ATF4 and Chop induction, Nrf2 activation and miRNA 211 in c-Myc-induced transformation in vitro and in vivo. In specific Aim 2, we will elucidate the mechanism of cytoprotection afforded by UPR activation in the context of oncogenic transformation by Myc. Under specific Aim 3, we will investigate the impact of c-Myc overexpression on the activation of the other two major UPR pathways. In specific Aim 4, we will determine the role of PERK activation in c-Myc induced lymphomagenesis using a transgenic mouse model. Successful completion of these studies would establish, for the first time, Myc upregulation as a cell-autonomous activator of UPR and would unveil novel targets for inhibiting Myc-dependent tumorigenesis. RELEVANCE (See instructions): The major oncogene c-Myc is activated in malignancies, including lymphomas, colorectal cancer and neuroblastomas. The Unfolded Protein Response (UPR) is increasingly been recognized as a mechanism of tumor resistance to stress and- promoter of tumorigenesis. Our preliminary findings suggest a novel role of UPR activation as an enhancer of tumorigenesis by c-Myc. Our proposed studies will investigate the mechanism of UPR activation by Myc in cell lines, animal tumor models and human samples and have the potential to lead to the development of novel therapeutics targeting Myc-dependent malignancies.