The contribution of protein translation to tumorigenesis

蛋白质翻译对肿瘤发生的贡献

• 批准号: 8595293
• 负责人: Hans-Guido Wendel
• 金额: $ 37.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595293
• 关键词: Apoptosis; Apoptotic; Area; Biology; Cancer Biology; Candidate Disease Gene; Cell Death; Cell Proliferation; Clinical; Clinical Trials; Collaborations; Development; Fractionation; Gene Expression; Genes; Genetic; Hospitals; Human; In Vitro; Individual; Lesion; Lymphocyte; Lymphoma; Maintenance; Malignant - descriptor; Malignant Neoplasms; Measures; Messenger RNA; Modeling; Mus; Oncogene Proteins; Oncogenic; Patients; Pharmaceutical Preparations; Polyribosomes; Principal Investigator; Production; Protein p53; Proteins; Publications; Qualifying; Recruitment Activity; Resistance; Ribosomes; Role; Sequence Analysis; Services; Signal Transduction; TP53 gene; Techniques; Testing; Therapeutic; Translating; Translational Activation; Translational Regulation; Translations; Tumor Biology; base; c-myc Genes; chemotherapy; clinical application; clinically relevant; deep sequencing; feeding; human FRAP1 protein; in vivo; inhibitor/antagonist; innovation; insight; mouse model; novel; pre-clinical; preclinical study; protein expression; public health relevance; research study; small molecule; tool; translation factor; tumor; tumorigenesis

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.

描述（由申请人提供）：我们已经证明激活蛋白质翻译可以驱动小鼠模型中的肿瘤发生。例如，eIF4E 翻译因子单独或与 c-Myc 一起可导致小鼠肿瘤发生。然而，目前尚不清楚增加的翻译究竟如何促进肿瘤的发展。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。我们将使用镶嵌小鼠淋巴瘤模型和先进的多核糖体分析技术在我们的提案中测试这一假设。我们之前使用小鼠淋巴瘤模型来显示翻译激活的致癌作用。在目标 1 中，我们将使用相同的小鼠模型在体内生成由翻译激活驱动或通过翻译独立机制产生的淋巴瘤。为了准确识别哪些 mRNA 优先翻译，我们将使用多核糖体分级分离和核糖体相关 mRNA 的深度测序。接下来，我们将在体外和小鼠模型中测试各个候选基因的肿瘤相关功能。值得注意的是，我们已经将抗凋亡 Mcl1 鉴定为第一个翻译控制的癌蛋白，并表征了其功能。这些实验现在将作为研究其他候选者的模板（参见初步研究和目标 2）。在目标 3 中，我们将使用我们的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 在一些人类淋巴瘤中高度表达，它对应于翻译激活标记。我们推测由翻译激活驱动的肿瘤可能表现出对 Mcl1 的需求增加。这项临床前试验是与纪念医院的淋巴瘤服务中心合作进行的，并将直接纳入他们对同一化合物的临床试验。 总之，这是一项针对肿瘤发生和治疗中翻译调控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测序技术以及我们的临床前试验具有近期临床应用的潜力。此外，我们最近在《基因与发育》上发表的文章表明了成功研究的记录，这些研究为肿瘤生物学这一尚未充分研究的领域提供了新的见解。

项目成果

Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.

• DOI: 10.1084/jem.20110846
• 发表时间: 2011-08-29
• 期刊: The Journal of experimental medicine
• 作者: Schatz JH;Oricchio E;Wolfe AL;Jiang M;Linkov I;Maragulia J;Shi W;Zhang Z;Rajasekhar VK;Pagano NC;Porco JA Jr;Teruya-Feldstein J;Rosen N;Zelenetz AD;Pelletier J;Wendel HG
• 通讯作者: Wendel HG

RiboDiff: detecting changes of mRNA translation efficiency from ribosome footprints.

• DOI: 10.1093/bioinformatics/btw585
• 发表时间: 2017-01-01
• 期刊: Bioinformatics (Oxford, England)
• 作者: Zhong Y;Karaletsos T;Drewe P;Sreedharan VT;Kuo D;Singh K;Wendel HG;Rätsch G
• 通讯作者: Rätsch G

Progress against follicular lymphoma.

• DOI: 10.1097/moh.0b013e3283622ed6
• 发表时间: 2013-07
• 期刊: Current opinion in hematology
• 影响因子: 3.2
• 作者: Schatz JH;Oricchio E;Puvvada SD;Wendel HG
• 通讯作者: Wendel HG

Functional genomics lead to new therapies in follicular lymphoma.

• DOI: 10.1111/nyas.12120
• 发表时间: 2013-07
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Oricchio E;Wendel HG
• 通讯作者: Wendel HG

Mouse models of cancer as biological filters for complex genomic data.

癌症小鼠模型作为复杂基因组数据的生物过滤器。

• DOI: 10.1242/dmm.006296
• 发表时间: 2010
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Oricchio,Elisa;Wolfe,AndrewL;Schatz,JonathanH;Mavrakis,KonstantinosJ;Wendel,Hans-Guido
• 通讯作者: Wendel,Hans-Guido