Novel Regulatory Factors of the Spindle Assembly Checkpoint

主轴装配检查点的新颖调节因素

基本信息

批准号：
9210112
负责人：
Jorge Torres
金额：
$ 34.65万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210112
关键词：
Address Anaphase Aneuploidy Antimitotic Agents Antineoplastic Agents Apoptotic Area Biochemical Biological Bypass Cancer Patient Cell Cycle Cell Death Cell Survival Cell division Cells Chromosomal Instability Chromosomes Complement Complex Cyclin-Dependent Kinases Development Drug resistance Effectiveness Ensure Enzymes Event Future Gene Expression Genetic Genetic Materials Genome Stability Human Kinetochores Lead Light Link Malignant Neoplasms Maps Metaphase Microscopy Microtubules Mitosis Mitotic spindle Modification Molecular Mothers Outcome Paclitaxel Pathway interactions Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Phosphorylation Play Poison Post-Translational Protein Processing Prometaphase Protein Dephosphorylation Proteins Proteomics Quality of life Recruitment Activity Research Resistance Role Set protein Sister Chromatid Small Interfering RNA Specificity Tertiary Protein Structure Testing Time anticancer research base cancer therapy daughter cell improved interdisciplinary approach neoplastic cell novel protein function protein protein interaction public health relevance repaired research study response transmission process tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Human cell division is a highly coordinated set of events that ensures the proper transmission of genetic material (chromosomes) from one mother cell to two newly formed cells. Chromosome missegregation during cell division can lead to aneuploidy (an aberrant chromosomal number), which is a hallmark of most cancers and has been proposed to promote tumorigenesis. Critical to ensuring proper sister chromatid separation at the metaphase to anaphase transition is the multi-component spindle assembly checkpoint (SAC), which is activated when unattached kinetochores or nonproductive (monotelic, syntelic, and merotelic) attachments are sensed and functions to arrest cells in metaphase to give time to correct these deficiencies and generate proper microtubule-kinetochore attachments before proceeding with cell division. Interestingly, a functional SAC plays a role in the effectiveness of chemotherapeutic drugs like antimitotics (drugs that inhibit mitosis), which damage the mitotic spindle, activate the SAC, arrest cells in prometaphase and trigger apoptotic cell death. Because understanding the SAC is critical to understanding tumorigenesis and the response of tumor cells to antimitotic drugs, it has become an attractive area of research. Although the last 40 years of research has shed light on the SAC, we are far from elucidating the full complement of regulatory factors involved in this complex pathway and from understanding how misregulation of this pathway can lead to tumorigenesis and resistance to chemotherapeutic drugs like antimitotics. To address these issues, we recently performed a high-throughput small interfering RNA (siRNA) screen for novel regulators of the SAC. This approach yielded two novel cyclin dependent kinases (Cdk14 and Cdk15) and two dual specificity phosphatases (DUSP7 and DUSP12). Inactivation of these novel factors leads to SAC bypass in the presence of antimitotic drugs like Taxol, which normally activate the SAC and induce cell death. To our knowledge, these factors have not been previously linked to SAC functioning and have limited genetic and molecular characterization in general. Thus understanding how these factors regulate the SAC is important to understanding the SAC and more broadly cell division. We hypothesize that these factors are controlling the SAC through their phosphorylation and dephosphorylation activities. Thus, we will test this hypothesis by analyzing the function of these proteins during unperturbed cell divisions and in the presence of antimitotics that generate spindle damage and activate the spindle assembly checkpoint. We expect that our studies will identify and characterize new factors and pathways that regulate the SAC, that we will be able to map their roles in time and space, and that our contributions to understanding the mechanisms of cell division will impact future cancer studies and cancer patient quality of life and survival.

描述（由适用提供）：人类细胞分裂是一组高度协调的事件，可确保遗传物质（染色体）从一个母细胞到两个新形成的细胞的正确传播。细胞分裂期间的染色体错误分类可以导致非整倍性（异常染色体数），这是大多数癌症的标志，并已提议促进肿瘤发生。多组分的纺锤体组装检查点（SAC），确保在中期与动画过渡时保持适当的姐妹染色质分离至关重要，当无辅助的动力学或非生产力（单型，syntellic和morotelic）附着在这些字体中，可以使这些字样和时间固定在形式中，并在固定的附加中，它会被激活。在进行细胞分裂之前。有趣的是，功能性SAC在有效性中发挥了作用化学治疗药物（例如抗激毒剂）（抑制有丝分裂的药物），损害有丝分裂主轴，激活囊囊，释放囊细胞，中期释放细胞并触发凋亡细胞死亡。因为了解SAC对于理解肿瘤发生和肿瘤细胞对抗魔法药物的反应至关重要，因此它已成为一个有吸引力的研究领域。尽管过去40年的研究已经阐明了SAC，但我们远没有阐明该复杂途径中涉及的调节因素的完整完成，也无法理解该途径的错过如何导致肿瘤发生和对化学治疗药物（如抗激素）的抗性。为了解决这些问题，我们最近为SAC的新调节剂进行了高通量小型干扰RNA（siRNA）屏幕。这种方法产生了两种新型细胞周期蛋白依赖性激酶（CDK14和CDK15）和两个双重特异性磷酸酶（DUSP7和DUSP12）。这些新因素的灭活导致在存在抗魔法药物（如紫杉醇）的情况下导致SAC绕过，这通常会激活SAC并诱导细胞死亡。据我们所知，这些因素以前尚未与SAC功能联系起来，并且总体上具有有限的遗传和分子表征。理解这些因素如何调节囊的方法对于了解囊和更广泛的细胞分裂很重要。我们假设这些因素通过其磷酸化和去磷酸化活性来控制SAC。那就是我们将通过分析这些假设来检验这一假设在不受干扰的细胞分裂过程中，在存在抗魔术的情况下会产生纺锤体损伤并激活纺锤体组装检查点。我们预计我们的研究将确定并表征调节SAC的新因素和途径，我们将能够在时间和空间中绘制其角色，并且我们对理解细胞分裂机制的贡献将影响未来的癌症研究和癌症患者的生活质量和生存质量。