Nek2 and NPM in centrosome amplification

Nek2 和 NPM 在中心体扩增中的作用

基本信息

批准号：
8447579
负责人：
Harold I Saavedra
金额：
$ 29.17万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447579
关键词：
Address Affect Aneuploidy Biological Assay Breast Breast Cancer Cell Cell Culture Techniques Cell Cycle Cell Line Cells Centrioles Centrosome Chromosomal Instability Cultured Cells Cyclin D1 Cyclins Data Defect Down-Regulation Epithelial Cells Etiology Frequencies Genetic Transcription Human Hyperplasia Image Lesion Licensing Life MAP Kinase Gene Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Mediator of activation protein Mitosis Modeling Mouse Mammary Tumor Virus Mus Mutation NPM1 gene Oncogenes Oncogenic Pathway interactions Patients Phase Phosphorylation Premalignant Proteins Publishing Regulation Rodent Signal Transduction Small Interfering RNA Source Testing Time Transgenic Mice base breast lesion c-myc Genes cancer initiation carcinogenesis genetic regulatory protein in vivo inhibitor/antagonist malignant breast neoplasm mutant overexpression premature prevent public health relevance tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Centrosome amplification, the acquisition of three or more centrosomes, results in defective spindles, multipolar mitosis and aneuploidy. Aneuploidy generates a plethora of genetic alterations that culminates in cancer initiation and promotion. Centrosome amplification is present in most human tumors, including 80-90% human breast cancers and precursor mammary lesions. How that centrosome amplification arises is based on correlative evidence; for example, human breast cancers over-expressing Her2 (30% of all human cancers) have high frequencies of centrosome amplification. In addition, many altered gene products involved in human cancers result in centrosome amplification and chromosome instability in cell culture. Our published results showed that Ras induced centrosome amplification through the MAPK pathway in cultured cells. Our preliminary data showed that Ras, but not c-Myc induces centrosome amplification in precursor mammary lesions. Expression assays showed that human and mouse mammary epithelial cells expressing Her2, or Ras display ectopically expressed cyclin D1 and Nek2. Down-regulation of cyclinD1, Cdk4 and Nek-2 prevent Her2 and Ras- dependent centrosome amplification. We propose the following hypothesis: The Her2/Ras pathway trigger centrosome amplification and mammary tumor initiation by through a classical pathway involving Cdk4 phosphorylation of NPM, and through an alternative pathway involving ectopically-expressed Nek2. In specific aim 1 we will distinguish between a classical and an alternative pathway to centrosome amplification. In specific aim 2 we will assess how the alternative pathway impinges on centrosome amplification. Specific aim 3 will address how interfering with the classical pathway in vivo prevents centrosome amplification in pre-malignancy and suppresses mammary tumorigenesis.

描述（由申请人提供）：中心体扩增，即获得三个或更多中心体，导致纺锤体缺陷、多极有丝分裂和非整倍性。非整倍体会产生大量的基因改变，最终导致癌症的发生和促进。中心体扩增存在于大多数人类肿瘤中，包括 80-90% 的人类乳腺癌和前体乳腺病变。中心体扩增是如何产生的基于相关证据；例如，过度表达 Her2 的人类乳腺癌（占所有人类癌症的 30%）具有高频率的中心体扩增。此外，许多与人类癌症有关的改变的基因产物会导致细胞培养中的中心体扩增和染色体不稳定。我们发表的结果表明，Ras 在培养细胞中通过 MAPK 途径诱导中心体扩增。我们的初步数据表明，Ras（而非 c-Myc）在前体乳腺病变中诱导中心体扩增。表达测定表明，表达 Her2 或 Ras 的人和小鼠乳腺上皮细胞显示异位表达的细胞周期蛋白 D1 和 Nek2。 cyclinD1、Cdk4 和 Nek-2 的下调可防止 Her2 和 Ras 依赖性中心体扩增。我们提出以下假设：Her2/Ras 途径通过涉及 NPM 的 Cdk4 磷酸化的经典途径和涉及异位表达的 Nek2 的替代途径触发中心体扩增和乳腺肿瘤起始。在具体目标 1 中，我们将区分中心体扩增的经典途径和替代途径。在具体目标 2 中，我们将评估替代途径如何影响中心体扩增。具体目标 3 将解决体内干扰经典途径如何防止癌前中心体扩增并抑制乳腺肿瘤发生的问题。