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：
9064727
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/9064727
关键词：
6q21 Ablation Acute Acute T Cell Leukemia Address Animals Automobile Driving Binding CDK3 gene Cell Proliferation Cells Complement Complementary DNA Complex Cyclin D1 Cyclin-Dependent Kinases Cyclins DNA Sequence Alteration Development Drosophila genus F-Box Proteins Funding Gene Expression Gene Targeting Genes Genetic Goals Growth Health 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 Mouse Strains Mus Mutation Null Lymphocytes Patients Phosphorylation Phosphotransferases Physiology Play Predisposition Process Proliferating Prostate Proteins PubMed Publishing Regulation Research Research Personnel Role Saccharomyces cerevisiae Sampling T-Lymphocyte Testing Tumor Cell Line Tumor Suppressor Proteins Ubiquitination Up-Regulation Work cancer cell cancer therapy cancer type cyclin C design embryonic stem cell in vivo leukemogenesis malignant breast neoplasm malignant stomach neoplasm mouse model notch protein novel 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（由适用提供）：该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Cyclin C在T细胞淋巴细胞白血病中的作用（T-All，在AIMS 1和2中），而在AIM 3中，我们将扩展分析到前列腺和肺癌。在20年前，将细胞周期蛋白C与细胞周期蛋白D1和E一起克隆，在哺乳动物和果蝇CDNA的筛选中可以补充酿酒酵母CLN1-3基因中的突变。随后，细胞周期蛋白D1和E进行了广泛的研究，并且它们参与癌症已经有充分的文献记载。相反，细胞周期蛋白在人类癌症中的作用知之甚少。为了分析细胞周期蛋白C在肿瘤发生中的功能，我们使用胚胎干细胞中的基因靶向产生了条件细胞周期蛋白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Notch1（ICN1）水平的强烈上调。我们观察到Cyclin C-CDK8激酶磷酸化ICN1，这又允许ICN1与F-box蛋白FBW7结合，并触发ICN1多泛素化和随后的蛋白质体降解。细胞周期蛋白C的消融会破坏这一过程，从而导致ICN1水平的强烈上调。对条件细胞周期蛋白C敲除小鼠的分析表明，这些动物表现出对T-all的敏感性提高。重要的是，细胞周期蛋白C杂合子还显示出增加肿瘤敏感性。此外，我们观察到细胞周期蛋白C基因在大部分人类T-All中被杂合删除，这些肿瘤显示出降低的细胞周期蛋白C水平。总的来说，这些观察结果表明，细胞周期蛋白可能在体内起作用，作为单倍抑制肿瘤抑制剂。在拟议的工作中，我们将扩展这些观察结果。在特定目标1中，我们将使用人肿瘤细胞系研究Cyclin C在T-ALL中的确切分子功能。在特定的目标2中，我们将利用主要的，患者来源的人类T型样品来寻找编码细胞周期蛋白C激酶伴侣的基因中的突变或缺失（Cyclin依赖性激酶CDK8，CDK19和CDK3）。在AIM 3中，我们将把研究扩展到前列腺和肺癌。