BubR1 in Cancer and Aging

描述（由申请人提供）：大多数人类癌症都有异常数量的染色体，称为非整倍体。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，直到所有着丝点都附着在有丝分裂纺锤体上，防止染色体错误分离。在某些非整倍体的人类癌症中，有丝分裂检查点基因BubR1中发现了遗传或表观遗传突变。在之前的资助期间，我们已经证明，低水平BubR1的突变小鼠会发生频繁的染色体错分离，并产生严重的非整倍体。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，在年轻时就出现了多种类早衰症特征，这表明BubR1可以预防癌症和衰老。最近在马赛克杂色非整倍体（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）患者中发现双等位基因BubR1突变，进一步支持了这一观点。当前提案的总体目标是了解BubR1控制衰老和癌症的机制。初步研究表明，当BubR1水平下降时，衰老反应基因p53、p21、p19和p16会被诱导，Mek-Erk信号通路在这一诱导过程中起作用。使用p16基因敲除小鼠，我们发现在BubR1亚型小鼠中，这种肿瘤抑制因子的缺失加速了肺肿瘤的发生，并阻止了一组年龄相关疾病的发展。在目的一中，我们建议使用p53， p19和p21敲除小鼠来解剖p53通路在bubr1介导的癌症和衰老中的作用。在aim 2中，我们将使用BubR1转基因小鼠来确定干预BubRt随年龄自然下降是否能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BubR1突变基因来确定该蛋白的哪些功能域是抑制癌症和衰老所必需的。我们还将确定MVA综合征是否由BubR1激酶活性受损引起。从这些研究中获得的信息将大大有助于我们了解癌症和衰老的分子遗传学基础。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。

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.