Mechanisms Controlling BubR1 Regulation of Cancer and Aging

摘要： 该提案的目标是阐明控制BubR 1蛋白丰度的分子机制， 功能及其在肿瘤发生和衰老调节中的作用。衰老是最大的风险因素 癌症的发展，但驱动这种相互关系的机制基础仍然在很大程度上不明确。BubR1， 丝氨酸/苏氨酸蛋白激酶，参与纺锤体组装检查点（SAC），以确保忠实的 在有丝分裂期间染色体分离，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，BubR 1在老化过程中，BubR 1的丰度一直是 随着哺乳动物年龄的增长，经工程改造以表达低水平BubR 1的小鼠 从出生一年内死亡，表现出增加的衰老，过早老化表型和增加的 对癌症的易感性，而过表达BubR 1的小鼠随着年龄的减少寿命延长， 相关疾病和癌症的发展。衰老被认为在很大程度上是肿瘤抑制性的， 预防年轻人的癌症然而，在老年人中，衰老细胞可以促进与年龄相关的衰老。 癌症发展因此，BubR 1可能在衰老和衰老之间的相互关系中发挥关键作用。 考虑到BubR 1抑制衰老和肿瘤发生，此前，我们发现了一个 乙酰化依赖性机制调节BubR 1蛋白的稳定性，其中SIRT 2阻止BubR 1蛋白的降解。 BubR 1通过去乙酰化，导致BubR 1早衰小鼠模型的寿命延长。 此外，通过刺激SIRT 2，老年动物中的BubR 1蛋白水平可以恢复到年轻水平。 通过诱导NAD+水平的活性。这些结果表明，年龄相关的BubR 1水平下降， 可以逆转，潜在地减轻与年龄有关的疾病，包括癌症。因此，我们假设， BubR 1是一种关键的肿瘤抑制因子，随着年龄的增长，它的丢失会增加癌症的易感性。在本提案中，我们 计划：1）阐明BubR 1翻译后修饰在衰老和卡路里代谢中的生理作用。 限制及其对有丝分裂进程和肿瘤发生的影响; 2）确定机制 在衰老过程中调节BubR 1蛋白的丰度和功能。这些研究将阐明如何调节 BubR 1通过翻译后修饰控制衰老过程中的有丝分裂进程和肿瘤发生 以确定BubR 1随年龄增长而下降并控制衰老过程的机制。给定 衰老是癌症发生的最大单一风险因素，阐明了控制癌症的分子细节， BubR 1在癌症和衰老中的生理作用将提供对癌症的机制性理解。 衰老和癌症发展之间的相互关系，以及确定可能的治疗策略， 治疗与年龄有关的疾病。

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.