TRIP13 AAA-ATPase overexpression in chromosomal instability and breast cancer

TRIP13 AAA-ATPase 在染色体不稳定和乳腺癌中过度表达

基本信息

批准号：
9262172
负责人：
Song-Tao Liu
金额：
$ 30.61万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262172
关键词：
ATP Hydrolysis ATP phosphohydrolase Adaptor Signaling Protein Address Affect Agar Anaphase Aneuploid Cells Aneuploidy Animals Automobile Driving Biochemical Breast Cancer Cell Breast Epithelial Cells Cancer Cell Growth Cell Line Cell Proliferation Cell Survival Cells Characteristics Chromosomal Instability Chromosomal Stability Complex Cultured Cells Cytogenetics Development Diagnosis Disadvantaged Drug Targeting Engineering Enzymes Epigenetic Process Exhibits Genes Genetic Genome Genome Stability Growth Investigation Kinetochores Knowledge MCF10A cells MXD1 gene MXI1 gene Macromolecular Complexes Malignant Neoplasms Metaphase Mitosis Mitotic Mitotic Checkpoint Modeling Molecular Mutation Neoplastic Cell Transformation Non-Malignant Nude Mice Oncogene Activation Oncogenic Outcome Pathologic Proteins Public Health Research Saccharomycetales Signal Transduction Solid Neoplasm TP53 gene Testing Tumor Suppressor Proteins Tumorigenicity Validation Work Xenograft procedure Yeasts base cancer cell cancer prevention cell growth cell transformation data mining experimental study fitness genetic signature innovation insight interest knock-down live cell imaging malignant breast neoplasm member mouse model neoplastic cell new therapeutic target novel novel anticancer drug outcome forecast overexpression premature protein complex public health relevance three dimensional cell culture tumor growth tumorigenesis tumorigenic

ATP Hydrolysis ATP phosphohydrolase Adaptor Signaling Protein Address Affect Agar Anaphase Aneuploid Cells Aneuploidy Animals Automobile Driving Biochemical Breast Cancer Cell Breast Epithelial Cells Cancer Cell Growth Cell Line Cell Proliferation Cell Survival Cells Characteristics Chromosomal Instability Chromosomal Stability Complex Cultured Cells Cytogenetics Development Diagnosis Disadvantaged Drug Targeting Engineering Enzymes Epigenetic Process Exhibits Genes Genetic Genome Genome Stability Growth Investigation Kinetochores Knowledge MCF10A cells MXD1 gene MXI1 gene Macromolecular Complexes Malignant Neoplasms Metaphase Mitosis Mitotic Mitotic Checkpoint Modeling Molecular Mutation Neoplastic Cell Transformation Non-Malignant Nude Mice Oncogene Activation Oncogenic Outcome Pathologic Proteins Public Health Research Saccharomycetales Signal Transduction Solid Neoplasm TP53 gene Testing Tumor Suppressor Proteins Tumorigenicity Validation Work Xenograft procedure Yeasts base cancer cell cancer prevention cell growth cell transformation data mining experimental study fitness genetic signature innovation insight interest knock-down live cell imaging malignant breast neoplasm member mouse model neoplastic cell new therapeutic target novel novel anticancer drug outcome forecast overexpression premature protein complex public health relevance three dimensional cell culture tumor growth tumorigenesis tumorigenic

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项目摘要

DESCRIPTION (provided by applicant): Aneuploidy and chromosomal instability (CIN) are remarkably common in solid tumors including breast cancers. Identifying and characterizing recurring genetic and epigenetic changes in aneuploid cancers will have tremendous impact on cancer prevention, diagnosis and treatment. TRIP13 was ranked as one of the top genes associated with CIN (#12 in the CIN70 signature), and its overexpression was also observed in breast cancers with poor prognosis in multiple microarray studies. However, the working mechanism of TRIP13 and the pathological significance of TRIP13 overexpression in breast cancer development remain unclear. Our preliminary work found that TRIP13, a member of the AAA-ATPases, is a novel kinetochore protein and directly interacts with mitotic checkpoint silencing protein p31comet. TRIP13 knockdown delayed metaphase-to- anaphase transition and significantly reduced breast cancer cell proliferation in 2D culture and soft agar plates. The objective of current proposal is to elucidate mitotic functions of TRIP13 and examine the relationship between TRIP13 overexpression and breast cancer development. The central hypothesis is that TRIP13 overexpression promotes untimely mitotic checkpoint silencing, driving CIN and cancer development in mammary epithelial cells. Three specific aims will test the central hypothesis. Aim 1 will assess biochemical functions of TRIP13 in the mitotic checkpoint. Specifically, we will test that TRIP13, through its interaction with p31comet and its ATPase activity disrupts protein complexes required for mitotic checkpoint signaling. In Aim 2, we will use inducible cell lines to modulate TRIP13 expression level and determine the impact on chromosomal stability and cell proliferation in 2D and 3D cell culture models. Aim 3 will examine the effects of TRIP13 overexpression or knockdown on breast cancer cell growth in xenografted mouse models. Together, the proposed work will test potential oncogenic functions of TRIP13 ATPase and assess the possibility to target TRIP13 as a novel means to control breast cancers. The work also addresses some critical knowledge gaps in mitotic checkpoint signaling studies. Dissecting TRIP13 functioning mechanisms represents an important step in our continuous efforts to understand and exploit aneuploidy and CIN in breast cancers.

描述（由申请人提供）：非整倍性和染色体不稳定性（CIN）在包括乳腺癌在内的实体瘤中非常常见。识别和表征非整倍体癌症的遗传和表观遗传变化，将对预防癌症，诊断和治疗产生巨大影响。 Trip13被评为与CIN相关的顶级基因之一（CIN70签名中的＃12），并且在多次微阵列研究中，在预后不良的乳腺癌中也观察到了其过表达。然而，Trip13的工作机制和TRIP13过表达在乳腺癌发育中的病理意义尚不清楚。我们的初步工作发现，AAA-ATPases的成员Trip13是一种新型的动力学蛋白，并直接与有丝分裂检查点沉默的蛋白p31comet相互作用。 TRIP13敲低延迟中期到后期的转变，并在2D培养和软琼脂平板中显着降低了乳腺癌细胞的增殖。当前建议的目的是阐明Trip13的有丝分裂功能，并检查Trip13过表达与乳腺癌发展之间的关系。中心假设是Trip13过表达促进了乳腺上皮细胞中过时的有丝分裂检查点沉默，驱动CIN和癌症的发展。三个具体目标将检验中心假设。 AIM 1将评估Trip13在有丝分裂检查点中的生化功能。具体而言，我们将通过与P31COMET的相互作用及其ATPase活性来测试TRIP13，会破坏有丝分裂检查点信号所需的蛋白质复合物。在AIM 2中，我们将使用诱导细胞系调节TRIP13表达水平，并确定对2D和3D细胞培养模型中染色体稳定性和细胞增殖的影响。 AIM 3将检查Trip13过表达或敲低对异种移植小鼠模型中乳腺癌细胞生长的影响。拟议的工作将共同测试TRIP13 ATPase的潜在致癌功能，并评估将TRIP13作为控制乳腺癌的新手段的可能性。这项工作还解决了有丝分裂检查点信号研究中的一些关键知识差距。解剖TRIP13功能机制是我们持续努力理解和利用乳腺癌中的非整倍性和CIN的重要步骤。