Role of RecQ Helicases to Prevent Senescence By c-Myc

RecQ 解旋酶在 c-Myc 预防衰老中的作用

• 批准号: 7614428
• 负责人: CARLA GRANDORI
• 金额: $ 30.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614428
• 关键词: Abnormal DNA Repair; Address; Age; Aging; Aging-Related Process; Antibodies; Applications Grants; B-Cell Lymphomas; Biological; Bypass; Cancer cell line; Cell Aging; Cell Cycle Arrest; Cell Cycle Kinetics; Cell Line; Cells; DNA Damage; DNA Repair; DNA biosynthesis; DNA damage checkpoint; Data; Dependence; Development; Doctor of Philosophy; Dominant-Negative Mutation; Fibroblasts; Gene Targeting; Genes; Genetic Transcription; Goals; Human; Immunofluorescence Immunologic; Incidence; Knockout Mice; Lymphoma; Lymphomagenesis; MYC gene; Malignant Neoplasms; Modeling; Monitor; Mus; Normal Cell; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Progeria; Property; Repair Complex; Replication Origin; Research Personnel; Role; Specificity; Stress; Structure; Symptoms; Testing; Therapeutic Uses; Transgenic Organisms; Tumor Cell Line; Tumor Suppressor Proteins; WRN gene; Werner Syndrome; Work; c-myc Genes; cancer cell; cancer therapy; cell growth; chemotherapeutic agent; chemotherapy; helicase; human WRN protein; in vivo; inhibitor/antagonist; insight; loss of function mutation; mouse model; neoplastic cell; novel therapeutic intervention; overexpression; premature; prevent; programs; research study; response; senescence; telomere; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The avoidance of senescence is an essential property of tumor cells. We are planning to determine the role played by the WRN and potentially related RecQ helicases in the avoidance of oncogene-induced senescence. In particular, we will focus on the c-Myc oncogene as we have shown that c-Myc stimulates transcription of the WRN gene and more important, that the WRN protein is required to avoid cellular senescence induced by c-Myc overexpression. Loss of function mutations of WRN causes a human premature progeria, Werner Syndrome (WS), whose symptoms mimic aspects of natural aging. Cells derived from WS patients also show premature senescence, indicating that the organismal phenotype might be due to accelerated cellular senescence. We hypothesize that WRN function is required for the avoidance of senescence of tumor cells and thus may represent an attractive therapeutic target for cancer treatment. WRN protein participates in DNA repair of abnormal structures generated during DNA replication and aggravated by drugs that cause a DNA replication block. Indeed the preliminary data indicate that the senescence response of WRN deficient cells upon c-Myc overexpression is due to DNA damage and resultant cellular checkpoint responses. In this proposal we plan to test this hypothesis, thus defining the mechanisms of WRN and c-Myc co-dependence. These experiments will involve use of cells derived from WS patients (commercially available) as well as a variety of approaches to interfere with function/or expression of WRN in normal human fibroblasts and in human cancer cell lines. Finally, to assess the role of WRN in tumor development in vivo we will employ an established c-Myc induced lymphoma model in mice together with WRN knock-out mice. Ultimately, our goal is to provide a rational to develop WRN inhibitors to be employed in new therapeutic approaches for cancer. Our proposal is relevant to aging providing information on the basic function of WRN, a gene clearly implicated in organismal aging, and it is also of importance for cancer by defining how cells bypass senescence under oncogenic stimulation. This grant proposal focus on the hypothesis, supported by our previous work, that a gene involved in human aging, called the Werner Syndrome gene, is also involved in the "aging" process of tumor cells. In fact, it is known that cells in our body also age. Old cells eventually stop dividing, a condition referred to as irreversible cell-cycle arrest". This is incompatible with tumor cell growth and thus cancer cells have devised ways of avoiding aging. Our previous work demonstrated that the presence of WRN gene was necessary to avoid aging of normal cells when they carry an activated cancer gene. Now we would like to directly test if inhibition of WRN function in cell lines derived from human cancers will cause tumor cells to age or to stop growing. If so, drug inhibitors of WRN function could be proposed for the treatment of cancer.

描述（由申请人提供）：避免衰老是肿瘤细胞的重要特性。我们计划确定WRN和潜在相关的RECQ解旋酶在避免癌基因引起的衰老中起起的作用。特别是，我们将关注C-Myc癌基因，因为我们已经证明C-MYC刺激WRN基因的转录，并且更重要的是，需要WRN蛋白来避免C-Myc过表达引起的细胞衰老。 WRN功能突变的丧失会导致人类早期，Werner综合征（WS），其症状模仿了自然衰老的方面。源自WS患者的细胞还显示过早衰老，表明该生物表型可能是由于细胞衰老加速引起的。我们假设避免肿瘤细胞衰老需要WRN功能，因此可能代表了癌症治疗的有吸引力的治疗靶点。 WRN蛋白参与DNA复制过程中产生的异常结构的DNA修复，并受到引起DNA复制阻滞的药物的加重。实际上，初步数据表明，C-MYC过表达中WRN缺乏细胞的衰老响应是由于DNA损伤和导致的细胞检查点响应引起的。在此提案中，我们计划检验该假设，从而定义WRN和C-MYC共同依赖性的机制。这些实验将涉及使用来自WS患者（可商购）的细胞以及各种干扰正常人成纤维细胞和人类癌细胞系中WRN功能/或表达的方法。最后，为了评估WRN在体内肿瘤发育中的作用，我们将与WRN敲除小鼠一起在小鼠中采用已建立的C-MYC诱导淋巴瘤模型。最终，我们的目标是提供一个合理的方法，以开发用于癌症的新治疗方法中使用的WRN抑制剂。我们的建议与提供有关WRN的基本功能的信息有关，WRN是一种与生物衰老有关的基因，并且通过定义细胞如何在致癌刺激下绕过衰老，对癌症也很重要。这项批准提案的重点是我们先前的工作支持的假设，即涉及人类衰老的基因（称为Werner综合征基因）也参与了肿瘤细胞的“衰老”过程。实际上，众所周知，我们体内的细胞也会变老。旧细胞最终停止分裂，这种疾病被称为不可逆的细胞周期停滞。正常细胞的老化携带激活的癌症基因时，我们想直接测试源自人类癌的细胞线的抑制作用，会导致肿瘤细胞年龄或停止生长。可以提出用于治疗癌症。