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The function of cyclin C in tumorigenesis

细胞周期蛋白C在肿瘤发生中的作用

基本信息

批准号：
9265805
负责人：
Peter Sicinski
金额：
$ 45.36万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265805
关键词：
6q21 Ablation Acute Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Animals Automobile Driving Binding CCNE1 gene CDK3 gene Cell Proliferation Cells Complement Complementary DNA Complex Cyclin A Cyclin D1 Cyclin-Dependent Kinases Cyclins DNA Sequence Development Drosophila genus FBXW7 gene Funding Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Growth Hematopoietic Heterozygote Human Knock-out Knockout Mice Laboratories Lesion Lung Adenocarcinoma Lymphoblastic Leukemia Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Modeling Molecular Molecular Analysis Mouse Strains Mus Mutation Null Lymphocytes Patients Phosphorylation Phosphotransferases Physiology Play Polyubiquitination Predisposition Process Proliferating Proteins PubMed Publishing Regulation Research Research Personnel Role Saccharomyces cerevisiae Sampling T-Lymphocyte Testing Tumor Cell Line Tumor Suppressor Proteins Up-Regulation Work cancer cell cancer therapy cancer type cyclin C cyclin G1 design embryonic stem cell in vivo leukemogenesis malignant breast neoplasm malignant stomach neoplasm mouse model notch protein novel public health relevance tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to elucidate the function of cyclin C in tumorigenesis. In the proposed work we will focus on the role for cyclin C in T-cell lymphoblastic leukemia (T-ALL, in Aims 1 and 2), while in Aim 3 we will extend our analyses to prostate and lung cancers. Cyclin C was cloned over 20 years ago, together with cyclins D1 and E, in a screen for mammalian and Drosophila cDNAs that can complement mutations in Saccharomyces cerevisiae CLN1-3 genes. Subsequently, cyclins D1 and E have been extensively studied, and their involvement in cancer has been extremely well documented. In contrast, the role of cyclin C in human cancer is much less understood. In order to analyze the function of cyclin C in tumorigenesis, we generated conditional cyclin C knockout mice, using gene targeting in embryonic stem cells. Unexpectedly, we found that an acute ablation of cyclin C in hematopoietic cells led to a strong upregulation of intracellular Notch1 (ICN1) levels. We observed that cyclin C-CDK8 kinase phosphorylates ICN1, which in turn allows binding of ICN1 to an F-box protein Fbw7, and triggers ICN1 poly-ubiquitination and subsequent proteosomal degradation. Ablation of cyclin C disrupts this process, leading to strong upregulation of ICN1 levels. Analyses of conditional cyclin C knockout mice revealed that these animals display increased susceptibility to T-ALL. Importantly, cyclin C heterozygotes also display increased tumor susceptibility. Moreover, we observed that the cyclin C gene is heterozygously deleted in a substantial fraction of human T-ALL, and these tumors display reduced cyclin C levels. Collectively, these observations suggest that cyclin C likely functions in vivo as a haploinsufficient tumor-suppressor. In the proposed work we will extend these observations. In Specific Aim 1, we will study the exact molecular function of cyclin C in T-ALL using human tumor cell lines. In Specific Aim 2, we will utilize primary, patient-derived human T-ALL samples to search for mutations or deletions in genes encoding cyclin C kinase partners (cyclin-dependent kinases CDK8, CDK19 and CDK3). In Aim 3, we will extend our studies to prostate and lung cancers.

描述（由申请人提供）：本项目的目的是阐明细胞周期蛋白C在肿瘤发生中的功能。在拟议的工作中，我们将重点关注细胞周期蛋白C在T细胞淋巴细胞白血病（T-ALL，在目标1和2）中的作用，而在目标3中，我们将把我们的分析扩展到前列腺癌和肺癌。细胞周期蛋白C在20多年前与细胞周期蛋白D1和E一起被克隆，用于筛选哺乳动物和果蝇的cDNA，这些cDNA可以补充酿酒酵母CLN 1 -3基因的突变。随后，细胞周期蛋白D1和E已被广泛研究，它们在癌症中的作用已得到很好的证明。相比之下，细胞周期蛋白C在人类癌症中的作用则知之甚少。为了分析细胞周期蛋白C在肿瘤发生中的作用，我们利用胚胎干细胞基因打靶技术建立了条件性细胞周期蛋白C基因敲除小鼠。出乎意料的是，我们发现造血细胞中细胞周期蛋白C的急性消融导致细胞内Notch 1（ICN 1）水平的强烈上调。我们观察到细胞周期蛋白C-CDK 8激酶磷酸化ICN 1，这反过来又允许ICN 1与F-box蛋白Fbw 7结合，并触发ICN 1多聚泛素化和随后的蛋白体降解。细胞周期蛋白C的消融破坏了这一过程，导致ICN 1水平的强烈上调。对条件性细胞周期蛋白C基因敲除小鼠的分析显示，这些动物对T-ALL的易感性增加。重要的是，细胞周期蛋白C杂合子也显示出增加的肿瘤易感性。此外，我们观察到细胞周期蛋白C基因在相当一部分人T-ALL中异源缺失，这些肿瘤显示细胞周期蛋白C水平降低。总的来说，这些观察结果表明，细胞周期蛋白C可能在体内作为一个单倍不足的肿瘤抑制剂的功能。在本书中，我们将扩展这些观察。在具体目标1中，我们将使用人类肿瘤细胞系研究细胞周期蛋白C在T-ALL中的确切分子功能。在特定目标2中，我们将利用原发性、患者来源的人T-ALL样本来搜索编码细胞周期蛋白C激酶伴侣（细胞周期蛋白依赖性激酶CDK 8、CDK 19和CDK 3）的基因的突变或缺失。在目标3中，我们将把研究扩展到前列腺癌和肺癌。