Mechanisms Controlling BubR1 Regulation of Cancer and Aging

BubR1 调节癌症和衰老的控制机制

• 批准号: 9897456
• 负责人: Brian J. North
• 金额: $ 12.39万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897456
• 关键词: Acetylation; Address; Age; Aging; Anaphase; Aneuploidy; Animals; Automobile Driving; Birth; Caloric Restriction; Cell Aging; Cells; Chromosome Segregation; Chromosomes; Deacetylase; Deacetylation; Development; Disease; Engineering; Ensure; Exhibits; Genetic Materials; Goals; Human; In Vitro; Incidence; Individual; Light; Link; Longevity; Malignant Neoplasms; Mammals; Mediating; Metaphase Plate; Mitosis; Mitotic; Modification; Molecular; Mus; Mutation; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Predisposition; Premature aging syndrome; Process; Protein-Serine-Threonine Kinases; Proteins; Regulation; Risk Factors; Rodent Model; Role; Signal Pathway; Therapeutic; Tissues; Tumor Suppressor Proteins; Ubiquitination; age related; aged; cancer therapy; genome integrity; in vivo; mouse model; overexpression; pleiotropism; prevent; segregation; senescence; therapeutic target; tumor; tumorigenesis

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.

抽象的： 该提案的目的是阐明有关BubR1蛋白质丰度的分子机制和 功能及其在调节肿瘤发生和衰老中的作用。衰老是最大的风险因素 癌症发展，但是推动这种相互关系的机械基础仍然很大不确定。 bubr1， 丝氨酸/苏氨酸蛋白激酶参与主轴组件检查站（SAC），以确保忠实 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，最近的研究已涉及BUBR1在BUBR1丰度的衰老过程中 随着哺乳动物的年龄，显示出多种组织的下降。设计为表达低水平的BUBR1的小鼠 从出生死亡一年之内，表现出衰老的增加，过早的衰老表型和增加 对癌症的敏感性，而过表达BUBR1的小鼠的寿命延长，年龄降低 - 相关疾病和癌症发展。据信，衰老在很大程度上是肿瘤抑制的 预防年轻人的癌症。但是，在老年人中，衰老细胞可能有助于与年龄有关 癌症发展。因此，bubr1可能在衰老和衰老之间的相互关系中起关键作用 鉴于BUBR1抑制了衰老和肿瘤发生，癌症。以前，我们确定了 乙酰化依赖性机制调节BUBR1蛋白稳定性，其中SIRT2防止降解 BUBR1通过脱乙酰化，导致BUBR1过早老化小鼠模型的寿命延长。 此外，通过刺激SIRT2，可以将老年动物的BUBR1蛋白水平恢复到年轻水平 通过诱导NAD+水平的活动。这些结果表明BUBR1水平与年龄相关的下降 可以逆转，可能减轻包括癌症在内的与年龄有关的疾病。因此，我们假设 BUBR1是一种关键的肿瘤抑制剂，其随着年龄的增长会增加癌症的敏感性。在这个建议中，我们 计划：1）阐明衰老和卡路里翻译后BUBR1的生理作用 限制及其对有丝分裂进展和肿瘤发生的影响； 2）确定机制 调节衰老过程中BUBR1蛋白丰度和功能。这些研究将阐明如何调节 BUBR1通过翻译后修饰控制了衰老期间有丝分裂进展和肿瘤发生 为了确定BUBR1随着年龄而下降并控制衰老过程的机制。给出 这种衰老是发展癌症的最大单一危险因素，阐明了分子细节 BUBR1在癌症和衰老中的生理作用将提供机械理解 衰老与癌症发展之间的相互关系，并确定可能的治疗策略 治疗与年龄有关的疾病。

项目成果

Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy.

• DOI: 10.1007/s11033-021-06665-7
• 发表时间: 2021-09
• 期刊: Molecular biology reports
• 影响因子: 2.8
• 作者: Ma Y;North BJ;Shu J
• 通讯作者: Shu J

Physiological relevance of post-translational regulation of the spindle assembly checkpoint protein BubR1.

纺锤体组装检查点蛋白 BubR1 翻译后调节的生理相关性。

• DOI: 10.1186/s13578-021-00589-2
• 发表时间: 2021-04-23
• 期刊: Cell & bioscience
• 影响因子: 7.5
• 作者: Bloom CR;North BJ
• 通讯作者: North BJ

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT.

• DOI: 10.1155/2021/6655417
• 发表时间: 2021
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Kumari N;Reabroi S;North BJ
• 通讯作者: North BJ

Cullin 3SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6.

• DOI: 10.18632/oncotarget.18141
• 发表时间: 2017-07-18
• 期刊: Oncotarget
• 作者: Tan Y;Ci Y;Dai X;Wu F;Guo J;Liu D;North BJ;Huo J;Zhang J
• 通讯作者: Zhang J