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Cdk-2 Independent role of cyclin E in Cell survival

Cdk-2 细胞周期蛋白 E 在细胞存活中的独立作用

基本信息

批准号：
8386932
负责人：
Alexandru Almasan
金额：
$ 29.66万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-23 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386932
关键词：
Affect Apoptosis Apoptotic Binding Biological Markers C-terminal Caspase Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cell Survival Cells Characteristics Chronic Lymphocytic Leukemia Cleaved cell Clinical Clinical Treatment Competitive Binding Cyclin E Cytosol DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis DNA-PKcs Data Ectopic Expression Epithelial Fibroblasts G22P1 gene Generations Genetic Models Genotoxic Stress Hematopoietic Hematopoietic Neoplasms Human Individual Investigation Ionizing radiation Knock-out Knowledge Ligase Lymphocyte Mammalian Cell Mediating Mitochondria Modeling Molecular Mutagens Nonhomologous DNA End Joining Nuclear Patients Phosphotransferases Play Process Proteasome Inhibition Proteasome Inhibitor Proteins Proteolysis Radiation Radiation Tolerance Radiation therapy Regulation Repair Complex Resistance Role Signal Transduction Site Small Interfering RNA Testing Therapeutic Tumor Cell Line Ubiquitination caspase-3 cell growth regulation chemotherapy cytochrome c established cell line human CCNE1 protein knock-down multicatalytic endopeptidase complex mutant neoplastic cell novel prevent repaired response

项目摘要

Cyclin E1 (CycE) represents an essential regulator of the mammalian cell cycle and DNA replication. Our studies have recently uncovered its new role in the cell survival of hematopoietic tumor cells. We found that CycE is cleaved proteolytically during apoptosis induced by typical genotoxic agents such as ionizing radiation. This cleavage is dramatic as it affects most cellular CycE and is characteristic to all human tumor hematopoietic cells we have examined, both established cell lines or primary, freshly isolated from human patients. This cleavage is important for apoptosis as expression of a cleavage-resistant CycE mutant blocks this process. CycE cleavage generates p18CycE, which is unable to bind Cdk2 or other known interactors of CycE. Our hypothesis, supported by preliminary data, is that CycE function is mediated by its interaction with Ku70, which we have identified as a novel p18CycE-binding partner. By binding to Ku70, p18CycE1 displaces Bax, leading to its activation. Indeed, p18CycE genesis coincides with Bax activation and loss of mitochondrial functions and the ensuing apoptosis is dependent on both Bax and Ku70, since it is prevented in cells rendered deficient in these proteins by knockout or siRNA-mediated knock-down. As Ku70 is a critical component of the nonhomologous end joining (NHEJ) DNA repair, our preliminary data indicate that the CycE fragment also affects the response to DNA damage and its repair. We will determine the mechanism by which p18CycE regulates apoptosis and DNA repair, in addition to inactivating CycE function. These studies are focused on a molecule that is unique in regulating all three responses to genotoxic stress: cell cycle control, DNA repair, and apoptosis. Our objective is to understand the regulation of CycE and derivative p18CycE following genotoxic stress and their impact on cells with differential radiation sensitivity. We seek to determine: 1) how the Ku70 interaction with p18CycE regulates cell survival, 2) the regulation and role of p18CycE1, 3) the therapeutic potential of p18CycE1. These investigations will establish the contribution to apoptosis of CycE1 independent of Cdk2. Our studies will increase our understanding of the mechanism by which CycE may provide a molecular switch by coordinating key responses to genotoxic stress, that include cell cycle control, DNA repair, and apoptosis that govern the radio- or chemotherapy-induced signals in clinical therapy.

细胞周期蛋白 E1 (CycE) 代表哺乳动物细胞周期的重要调节因子 DNA复制。我们的研究最近发现了它在细胞存活中的新作用造血肿瘤细胞。我们发现 CycE 在由典型的基因毒性剂（例如电离辐射）诱导的细胞凋亡。这个乳沟具有戏剧性，因为它影响大多数细胞 CycE，并且是所有人类肿瘤的特征我们检查过的造血细胞，包括已建立的细胞系或原代的、新鲜的与人类患者分离。这种切割对于细胞凋亡很重要，因为抗切割 CycE 突变体阻断了这一过程。 CycE 裂解产生 p18CycE，无法结合 Cdk2 或其他已知的 CycE 相互作用子。我们的初步数据支持的假设是 CycE 功能是由其介导的与 Ku70 相互作用，我们已将其确定为新型 p18CycE 结合伴侣。经过与 Ku70 结合后，p18CycE1 取代 Bax，导致其激活。事实上，p18CycE 发生与 Bax 激活和线粒体功能丧失同时发生随后发生的细胞凋亡取决于 Bax 和 Ku70，因为它在细胞中被阻止通过基因敲除或 siRNA 介导的基因敲低，使这些蛋白质缺乏。作为 Ku70 是非同源末端连接 (NHEJ) DNA 修复的关键组成部分，我们的初步数据表明 CycE 片段也会影响对 DNA 的反应损坏及其修复。我们将确定 p18CycE 的调节机制除了使 CycE 功能失活之外，还可以促进细胞凋亡和 DNA 修复。这些研究是专注于调节对基因毒性的所有三种反应的独特分子应激：细胞周期控制、DNA 修复和细胞凋亡。我们的目标是了解基因毒性胁迫后 CycE 和衍生物 p18CycE 的调节及其影响对具有不同辐射敏感性的细胞。我们试图确定：1）Ku70 如何与 p18CycE 的相互作用调节细胞存活，2) p18CycE1 的调节和作用， 3）p18CycE1的治疗潜力。这些调查将确定 CycE1 对细胞凋亡的贡献不依赖于 Cdk2。我们的学习将增加我们的了解 CycE 提供分子开关的机制 coordinating key responses to genotoxic stress, that include cell cycle control, DNA 修复和细胞凋亡控制临床中放疗或化疗诱导的信号治疗。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

DOI：
10.1111/bjh.12498
发表时间：
2013-10
期刊：
British journal of haematology
影响因子：
6.5
作者：
Bodo J;Zhao X;Sharma A;Hill BT;Portell CA;Lannutti BJ;Almasan A;Hsi ED
通讯作者：
Hsi ED

The TMPRSS2-ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition.

DOI：
10.1158/1535-7163.mct-14-0865
发表时间：
2015-08
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Chatterjee P;Choudhary GS;Alswillah T;Xiong X;Heston WD;Magi-Galluzzi C;Zhang J;Klein EA;Almasan A
通讯作者：
Almasan A

Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas.