BubR1 in Cancer and Aging

BubR1 在癌症和衰老中的作用

• 批准号: 7322952
• 负责人: JAN M. VAN DEURSEN
• 金额: $ 30.14万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322952
• 关键词: Actins; Age; Aging; Anaphase; Aneuploidy; Arrhythmia; Binding; Bypass; CDKN1A gene; Carcinogens; Cataract; Cell Aging; Cells; Chemicals; Chromosomes; Complex; Data; Development; Disease; Dwarfism; Elderly; Epigenetic Process; Exhibits; Fatty acid glycerol esters; Funding; Genes; Genetic; Health; Human; Impaired wound healing; Intervention; Kinetochores; Knockout Mice; Knowledge; Longevity; Malignant Neoplasms; Mediating; Medical Surveillance; Mitotic Checkpoint; Mitotic spindle; Molecular; Molecular Genetics; Mosaic variegated aneuploidy syndrome; Mus; Muscular Atrophy; Mutant Strains Mice; Mutate; Mutation; Numbers; Pathway interactions; Patients; Personal Satisfaction; Phenotype; Phosphotransferases; Play; Predisposition; Premature aging syndrome; Progeria; Protein Overexpression; Relative (related person); Research Personnel; Role; Series; Signal Pathway; Signal Transduction; Spinal Curvatures; TP53 gene; Tertiary Protein Structure; Tissues; Transgenes; Transgenic Mice; Tumor Suppressor Proteins; Wild Type Mouse; age related; base; cancer cell; cell transformation; craniofacial; driving force; improved; lung tumorigenesis; malignant phenotype; mutant; novel strategies; oncoprotein p21; prevent; programs; promoter; response; sarcopenia; senescence; subcutaneous; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Most human cancers have abnormal numbers of chromosomes, known as aneuploidy. However, the causes of aneuploidy and its role in tumor development remain poorly understood. The mitotic checkpoint is a surveillance mechanism that prevents missegregation of chromosomes by delaying anaphase onset until all kinetochores have attached to the mitotic spindle. In certain human cancers with aneuploidy, genetic or epigenetic mutations have been identified in the mitotic checkpoint gene BubR1. During the previous funding period, we have shown that mutant mice with low levels of BubR1 undergo frequent chromosome missegregation and develop severe aneuploidy. These mice were more susceptible to carcinogen-induced tumorigenesis and, unexpectedly, developed a variety of progeroid features at young ages, suggesting that BubR1 prevents both cancer and aging. The recent discovery of biallelic BubR1 mutations in patients with mosaic variegated aneuploidy (MVA) syndrome, a recessive disorder characterized by aneuploidy, tumor susceptibility and progeroid features, further supports this idea. The overall objective of the current proposal is to understand the mechanisms by which BubR1 governs aging and cancer. Preliminary studies show that the senescence response genes p53, p21, p19 and p16 are induced when BubR1 levels decline and that the Mek-Erk signaling pathway plays a role in this induction. Using p16 knockout mice, we show that loss of this tumor suppressor accelerates lung tumorigenesis and prevents development of a subset of age-related disorders in BubR1 hypomorphic mice. In aim one, we propose to use p53, p19 and p21 knockout mice to dissect the role of the p53 pathway in BubR1-mediated cancer and aging. In aim 2, we will use BubR1 transgenic mice to determine whether intervention in the natural decline of BubRt with age prevents tumorigenesis and aging-related disorders. In aim three we will use a series of BubR1 mutant transgenes to determine which functional domains of the protein are required for suppression of cancer and aging. We will also establish whether MVA syndrome is due to impaired BubR1 kinase activity. The information gained from these studies will significantly contribute to our understanding of the molecular genetic basis of cancer and aging. Knowledge gained from these efforts could be exploited to devise novel strategies for treatment of these interrelated disorders.

描述（由申请人提供）：大多数人类癌症具有异常数量的染色体，称为非整倍性。然而，非整倍体的原因及其在肿瘤发展中的作用仍然知之甚少。有丝分裂检查点是一种监视机制，通过延迟后期开始直到所有动粒都附着在有丝分裂纺锤体上来防止染色体的错误分离。在某些具有非整倍性的人类癌症中，已在有丝分裂检查点基因BubR 1中鉴定出遗传或表观遗传突变。在之前的资助期间，我们已经表明，BubR 1水平低的突变小鼠发生频繁的染色体错误分离，并发展为严重的非整倍体。这些小鼠更容易受到致癌物诱导的肿瘤发生的影响，并且出乎意料的是，在年轻时就出现了各种各样的早衰症特征，这表明BubR 1可以预防癌症和衰老。最近在镶嵌杂色非整倍体（MVA）综合征（一种以非整倍体、肿瘤易感性和早衰特征为特征的隐性疾病）患者中发现的双等位基因BubR 1突变进一步支持了这一观点。目前提案的总体目标是了解BubR 1控制衰老和癌症的机制。初步研究表明，当BubR 1水平下降时，衰老反应基因p53、p21、p19和p16被诱导，Mek-Erk信号通路在这种诱导中起作用。使用p16基因敲除小鼠，我们表明，这种肿瘤抑制因子的损失加速肺肿瘤的发生，并防止发展的一个子集的年龄相关性疾病的BubR 1低形态小鼠。在目标一中，我们建议使用p53，p19和p21基因敲除小鼠来剖析p53通路在BubR 1介导的癌症和衰老中的作用。在目标2中，我们将使用BubR 1转基因小鼠来确定干预BubRt随年龄的自然下降是否可以预防肿瘤发生和衰老相关疾病。在目标三中，我们将使用一系列BubR 1突变转基因来确定抑制癌症和衰老所需的蛋白质功能结构域。我们还将确定MVA综合征是否是由于BubR 1激酶活性受损。从这些研究中获得的信息将大大有助于我们理解癌症和衰老的分子遗传基础。从这些努力中获得的知识可以用来设计治疗这些相互关联的疾病的新策略。