The role of deregulated protein synthesis control in Myc-induced tumorigenesis

描述（由申请人提供）：在Myc诱导的肿瘤发生中，蛋白合成控制失调的作用Myc活性失调是人类癌症中最常见的致癌病变之一。这项提议的长期目标是阐明myc依赖性蛋白合成增加如何导致肿瘤形成的分子和细胞基础。Myc通过控制多种蛋白质合成机制组分的表达，包括核糖体蛋白、翻译起始因子、Pol III和rDNA，直接提高蛋白质合成率。myc依赖性增加在导致癌症的多步骤过程中的蛋白质合成中的作用仍然未知。我们利用核糖体蛋白杂合子小鼠作为遗传工具，在E<-Myc/+小鼠中选择性地恢复准确的蛋白质合成控制，并表明在这种情况下Myc的致癌潜力被抑制。我们的研究结果表明，Myc增加蛋白质合成的能力直接增加了细胞大小，并且足以独立于Myc转录调节的已知细胞周期靶点加速细胞周期进程。此外，当蛋白质合成恢复到正常水平时，myc过表达的癌前细胞被程序性细胞死亡更有效地消除。这些发现从遗传学上首次证明Myc致癌信号下游蛋白合成的增加在肿瘤发生中具有直接和因果作用。我们进一步表明，持续刺激myc超激活下游的帽依赖翻译特异性地损害了帽依赖翻译和内部核糖体进入位点（IRES）依赖翻译之间的转换，这是准确有丝分裂过程所必需的。在E<-Myc/+小鼠中，这种翻译开关失败导致细胞质分裂失败，并与基因组不稳定性增加有关。总之，这些发现强烈表明，Myc致癌信号传导可能垄断翻译机制，从而引发细胞生长、细胞周期进展和基因组不稳定性的协同作用，作为癌症起始的机制。这些结果为本研究的目标奠定了基础，本研究的重点是理解翻译控制中myc依赖性扰动如何在基因表达、基因组稳定性和癌症发生方面提供高度特异性的结果。在目标1中，我们将定义细胞生长增加的机制，作为蛋白质合成增强的结果，促进Myc超激活下游的细胞分裂。在目标2中，我们将评估淋巴瘤形成过程中eIF4E过度激活的必要性，以及致癌Myc信号下游基因组不稳定的有丝分裂翻译失败。最后，在Aim 3中，我们将定义myc诱导的细胞竞争在癌症发展中的作用。公共卫生相关性：本提案的目的是阐明myc依赖性蛋白合成增加导致肿瘤形成的机制。Myc是人类癌症中最常被解除管制的致癌基因。我们的工作可以帮助改进因蛋白质合成控制中断而发展为癌症的患者的诊断和治疗。

DESCRIPTION (provided by applicant): The role of deregulated protein synthesis control in Myc-induced tumorigenesis Deregulation of Myc activity is one of the most frequent oncogenic lesions underlying human cancers. The long-term objective of this proposal is to elucidate the molecular and cellular basis for how Myc-dependent increases in protein synthesis lead to tumor formation. Myc directly increases protein synthesis rates by controlling the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III and rDNA. The role of Myc-dependent increases in protein synthesis towards the multi-step process leading to cancer remains unknown. We utilized ribosomal protein heterozygote mice as a genetic tool to selectively restore accurate protein synthesis control in E<-Myc/+ mice and show that in this context Myc's oncogenic potential is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. These findings genetically demonstrate for the first time that an increase in protein synthesis downstream of Myc oncogenic signaling has a direct and causal role in tumorigenesis. We further show that the continuous stimulation of cap-dependent translation downstream of Myc-hyperactivation specifically impairs the translational switch between cap- and internal ribosomal entry site (IRES)-dependent translation required for accurate mitotic progression. This translational switch failure leads to cytokinesis failure and is associated with increased genome instability in E<-Myc/+ mice. All together, these findings strongly suggest that Myc oncogenic signaling may monopolize the translational machinery to elicit cooperative effects on cell growth, cell cycle progression, and genome instability as a mechanism for cancer initiation. These results lay the foundation for the goals of this proposal centered on understanding how Myc-dependent perturbations in translational control provide a highly specific outcome on gene expression, genome stability, and cancer initiation. In Aim 1 we will define the mechanism(s) by which increased cell growth, as a consequence of augmented protein synthesis, promotes cell division downstream of Myc hyperactivation. In Aim 2 we will assess the requirement of eIF4E hyperactivation in lymphomagenesis and the mitotic translational failure that underlies genome instability downstream of oncogenic Myc signaling. Finally, in Aim 3 we will define the role of Myc-induced cell competition in cancer development. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to elucidate the mechanisms by which Myc-dependent increases in protein synthesis lead to tumor formation. Myc is the most frequently deregulated oncogene in human cancers. Our work could help to refine diagnosis and therapy for patients that develop cancer as a consequence of disruptions in protein synthesis control.