The contribution of protein translation to tumorigenesis

描述（由申请人提供）：我们已经证明激活蛋白质翻译可以在小鼠模型中驱动肿瘤发生。例如，eIF4E翻译因子可以在单独或携带c-Myc的小鼠中引起肿瘤发展。然而，目前尚不清楚增加的翻译是如何促进肿瘤发展的。我们推测，翻译的激活直接增加了特异性抗凋亡和致癌活性的产生。我们将在我们的建议中使用马赛克小鼠淋巴瘤模型和先进的多核糖体分析技术来验证这一假设。我们先前使用小鼠淋巴瘤模型来显示翻译激活的致癌作用。在Aim 1中，我们将使用相同的小鼠模型在体内产生由翻译激活驱动或通过翻译无关机制产生的淋巴瘤。为了准确地确定哪些mrna被优先翻译，我们将使用多核糖体分离和核糖体相关mrna的深度测序。接下来，我们将在体外和小鼠模型中测试单个候选基因的肿瘤相关功能。值得注意的是，我们已经确定了抗凋亡的Mcl1是第一个翻译控制的癌蛋白，并描述了它的功能。这些实验现在将作为研究其他候选物质的模板（见初步研究和目标2）。在Aim 3中，我们将使用临床前淋巴瘤模型来测试用小分子（obatoclax）阻断Mcl1的治疗效果。Mcl1在一些人淋巴瘤中高度表达，它对应于翻译激活的标记物。我们推测由翻译激活驱动的肿瘤可能显示对Mcl1的需求增加。这项临床前试验是与纪念医院淋巴瘤服务部合作进行的，并将直接纳入他们对同一化合物的临床试验。总之，这是一项关于肿瘤发生和治疗中翻译调节的生物学和临床相关性的创新研究。所有必要的工具都已到位，例如马赛克小鼠模型，多核糖体分离和454测序技术，我们的临床前试验具有近期临床应用的潜力。此外，我们最近发表在《基因与发育》杂志上的文章表明，我们成功的研究记录为这一尚未充分研究的肿瘤生物学领域提供了新的见解。

DESCRIPTION (provided by applicant): We have shown that activating protein translation can drive tumorigenesis in mouse models. For example, the eIF4E translation factor can cause tumor development in mice alone or with c-Myc. However, it is unclear exactly how increased translation can promote tumor development. We speculate that the activation of translation directly increases the production of specific anti-apoptotic and oncogenic activities. We will test this hypothesis in our proposal using a mosaic mouse lymphoma model and advanced polyribosome profiling techniques. We previously used a mouse lymphoma model to show the oncogenic effect of translational activation. In Aim 1 we will use the same mouse model to generate lymphomas in vivo that are driven by translational activation or arise through a translation-independent mechanism. To identify exactly which mRNAs are preferentially translated, we will then use polyribosome fractionation and deep sequencing of ribosome-associated mRNAs. Next, we will test the tumor relevant functions of individual candidate genes in vitro and in our mouse model. Notably, we have identified the anti-apoptotic Mcl1 as a first translationally controlled oncoprotein, and have characterized its function. These experiments will now serve as a template for the study of additional candidates (see preliminary studies and Aim 2). In Aim 3 we will use our preclinical lymphoma model to test the therapeutic benefit of blocking Mcl1 with small molecule (obatoclax). Mcl1 is highly expressed in some human lymphomas, where it corresponds to markers of translational activation. We speculate that tumors driven by translational activation may show an increased requirement for Mcl1. This preclinical trial is in collaboration with the Lymphoma Service at Memorial Hospital, and will directly feed into their clinical trial on the same compound. Together, this is an innovative study into the biology and clinical relevance of translational regulation in tumorigenesis and therapy. All the necessary tools are in place, e.g. the mosaic mouse model, polyribosome fractionation and 454 sequencing techniques, and our preclinical trial has the potential for near term clinical application. Moreover, our recent publications in Genes & Development indicate a track record of successful studies that have provided new insights in this understudied area of tumor biology. PUBLIC HEALTH RELEVANCE: Cancer is caused by genetic activation cellular signals that drive cell proliferation and oppose cell death. Ultimately, these signals converge on downstream effectors that carry out these functions, these are most often proteins. Our study will characterize changes in protein production ("translation") in cancer. A first protein that we have found to be controlled at the level of protein production is Mcl1, which is highly produced in lymphocyte cancers (lymphoma) and makes these tumors resistant to cell death. Notably, a drug that can inhibit this protein exists and we will now test its effect against lymphomas in mice. We speculate that this drug should increase the ability of chemotherapy to induce cell death in tumors. This preclinical trial is the first step to determine whether the drug is suitable for patients, and we are conducting these studies in collaboration with the clinical lymphoma department of Memorial Hospital, so that our results can directly feed into clinical trials. In the long-term, we expect to find other proteins that behave like Mcl1, for most proteins a drug will not yet be available and our study will help define priorities for developing new drugs.