Mechanisms Controlling BubR1 Regulation of Cancer and Aging

摘要： 这项建议的目的是阐明控制BubR1蛋白丰度和 功能，以及它在调节肿瘤发生和衰老中的作用。老龄化是患糖尿病的唯一最大风险因素 癌症的发展，然而驱动这种相互关系的机制基础在很大程度上仍然是未知的。BubR1， 丝氨酸/苏氨酸蛋白激酶参与纺锤体组装检查点(SAC)，以确保 有丝分裂过程中的染色体分离，因此与基因组完整性和癌症密切相关。 有趣的是，最近的研究表明BubR1与衰老过程有关，而BubR1的丰度 随着哺乳动物年龄的增长，各种组织中的蛋白质含量都会下降。经过改造的小鼠表达低水平的BubR1 从出生死亡一年内，表现出衰老加剧，早衰表型和增加 对癌症的易感性，而过度表达BubR1的小鼠随着年龄的降低而寿命延长- 相关疾病和癌症的发展。衰老被认为在很大程度上是抑制肿瘤和 预防年轻人患癌症。然而，在老年人中，衰老细胞可以促进与年龄相关的 癌症的发展。因此，BubR1可能在衰老与衰老的相互关系中起着关键作用。 癌症，因为BubR1既能抑制衰老又能抑制肿瘤发生。之前，我们确定了一个 调节BubR1蛋白稳定性的乙酰化依赖机制，其中SIRT2防止降解 BubR1通过去乙酰化，导致BubR1早衰小鼠模型的寿命延长。 此外，通过刺激SIRT2，老年动物的BubR1蛋白水平可以恢复到年轻时的水平 通过诱导NAD+水平发挥活性。这些结果表明，与年龄相关的BubR1水平下降 可以逆转，有可能缓解包括癌症在内的与年龄相关的疾病。因此，我们假设 BubR1是一种关键的肿瘤抑制因子，随着年龄的增长，它的缺失会增加癌症的易感性。在这项提案中，我们 计划：1)阐明BubR1翻译后修饰在衰老和卡路里中的生理作用 限制及其对有丝分裂进程和肿瘤发生的影响；以及2)确定机制 在衰老过程中调节BubR1蛋白的丰度和功能。这些研究将阐明如何监管 BubR1通过翻译后修饰控制着有丝分裂的进展和衰老过程中的肿瘤发生 以确定BubR1随年龄增长而衰退并控制衰老过程的机制。vt.给出 衰老是患癌症的最大单一风险因素，阐明了导致癌症的分子细节 BubR1在癌症和衰老中的生理作用将提供对 老龄化与癌症发展之间的相互关系，以及确定可能的治疗策略 治疗年龄相关的疾病。

Abstract: The goal of this proposal is to elucidate the molecular mechanisms governing BubR1 protein abundance and function, and its role in the regulation of tumorigenesis and aging. Aging is the single greatest risk factor for cancer development, yet the mechanistic basis driving this interrelationship remains largely undefined. BubR1, a serine/threonine protein kinase, is involved in the spindle assembly checkpoint (SAC) to ensure faithful chromosome segregation during mitosis, and therefore is intimately linked to genomic integrity and cancer. Interestingly, recent studies have implicated BubR1 in the aging process where BubR1 abundance has been shown to decline in a variety of tissues as mammals age. Mice engineered to express low levels of BubR1 from birth die within a year, exhibiting increased senescence, premature aging phenotypes and an increased susceptibility to cancer, whereas mice overexpressing BubR1 have an extended lifespan with reduction in age- related diseases and cancer development. Senescence is believed to be largely tumor-suppressive and prevent cancer in young individuals. However, in aged individuals senescent cells can contribute to age-related cancer development. Therefore, BubR1 may play a pivotal role in the interrelationship between aging and cancer given that BubR1 suppresses both senescence and tumorigenesis. Previously, we identified an acetylation-dependent mechanism regulating BubR1 protein stability, where SIRT2 prevents degradation of BubR1 through deacetylation, leading to lifespan extension of a BubR1 premature aging mouse model. Furthermore, BubR1 protein levels in aged animals can be restored to youthful levels by stimulating SIRT2 activity through induction of NAD+ levels. These results suggest that the age-related decline in BubR1 levels can be reversed, potentially alleviating age-related diseases including cancer. Therefore, we hypothesize that BubR1 is a key tumor suppressor, and its loss with age increases cancer susceptibility. In this proposal, we plan to: 1) elucidate the physiological role of BubR1 post translational modifications during aging and calorie restriction and their impact on mitotic progression and tumorigenesis; and 2) determine the mechanisms regulating BubR1 protein abundance and function during aging. These studies will elucidate how regulation of BubR1 by post-translational modifications controls mitotic progression and tumorigenesis during aging as well as to identify mechanisms through which BubR1 declines with age and controls the aging processes. Given that aging poses the largest single risk factor for developing cancer, elucidating the molecular details governing the physiological role of BubR1 in cancer and aging will provide mechanistic understanding of the interrelationship between aging and cancer development, as well as identify possible therapeutic strategies to treat age-related diseases.