Normal and Neoplastic Regulation of Cyclin E
细胞周期蛋白 E 的正常和肿瘤调节
基本信息
- 批准号:6916340
- 负责人:
- 金额:$ 38.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-07-01 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:adeno associated virus groupantibodycarcinogenesiscell growth regulationcyclinsdisease /disorder modelfibroblastsgene mutationgene targetinggenetically modified animalshuman tissueimmunologic substance development /preparationlaboratory mousemodel design /developmentmolecular oncologyneoplastic growthp53 gene /proteinphosphorylationprotein protein interactionprotein structure functiontransfection /expression vectorubiquitin
项目摘要
DESCRIPTION (provided by applicant): The cyclin E protein controls the transition from the G1 to the S-phase of the cell cycle. Deregulated cyclin E activity causes abnormal cell division, and mutations leading to aberrant cyclin E-cdk2 regulation are found in most human cancers. The research described in this proposal seeks to understand the mechanisms that govern cyclin E in normal cells and tumors. We are particularly interested in the regulation and function of cyclin E phosphorylation in cell cycle control and tumorigenesis. Multiple site-specific phosphorylations control cyclin E, but the role of specific mitogenic and signal transduction pathways in regulating these phosphorylations is unknown. The goal of the first aim is to characterize the regulation of cyclin E phosphorylation in normal cells and in tumor cells. We will develop antibodies that recognize phosphorylated forms of cyclin E, and these reagents will be used to examine cyclin E phosphorylation in normal cells, and to determine if it is abnormal in tumor cells. We are particularly interested in the relationships between phosphorylated cyclin E and the Fbw7 ubiquitin ligase. Because most studies on cyclin E phosphorylation have utilized overexpressed cyclin E, it has been difficult to distinguish the role of phosphorylation from the consequences of overexpression. We will thus use "knock-in" models in which phosphorylation sites are mutated in the context of the endogenous cyclin E locus to study the function of specific phosphorylations. These studies will use homologous recombination techniques in mice, as well as develop new methods based on adeno-associated virus vectors in human cells. The latter method may be broadly applicable to studies of protein phosphorylation in systems where mouse models are unnecessary or undesirable. The mechanisms of cyclin E-associated tumorigenesis are largely unknown. The overall goal of this aim is to use cyclin E transgenic and knock-in strains to develop models of cyclin E-associated cancer. Because we have discovered a homeostatic p53-dependent response that restrains excess cyclin E activity, we will specifically test the hypothesis that loss of p53 function is an integral step in the development of tumors with deregulated cyclin E expression. These models will be used to study the mechanisms of cyclin E-associated tumorigenesis and may facilitate the development of new therapeutic strategies.
描述(由申请人提供):细胞周期蛋白E控制细胞周期从G1期到S期的转变。细胞周期蛋白E活性失调导致细胞分裂异常,导致细胞周期蛋白E-cdk 2调节异常的突变在大多数人类癌症中发现。该提案中描述的研究旨在了解正常细胞和肿瘤中控制细胞周期蛋白E的机制。我们对细胞周期蛋白E磷酸化在细胞周期控制和肿瘤发生中的调节和功能特别感兴趣。多个位点特异性磷酸化控制细胞周期蛋白E,但特定的促有丝分裂和信号转导途径在调节这些磷酸化的作用是未知的。第一个目标是表征正常细胞和肿瘤细胞中细胞周期蛋白E磷酸化的调节。我们将开发识别磷酸化形式的细胞周期蛋白E的抗体,这些试剂将用于检查正常细胞中的细胞周期蛋白E磷酸化,并确定它在肿瘤细胞中是否异常。我们特别感兴趣的磷酸化细胞周期蛋白E和Fbw 7泛素连接酶之间的关系。 由于大多数关于细胞周期蛋白E磷酸化的研究都是利用过表达的细胞周期蛋白E,因此很难区分磷酸化的作用和过表达的后果。因此,我们将使用“敲入”模型,其中磷酸化位点在内源性细胞周期蛋白E基因座的背景下发生突变,以研究特定磷酸化的功能。这些研究将在小鼠中使用同源重组技术,并在人类细胞中开发基于腺相关病毒载体的新方法。后一种方法可广泛适用于在不需要或不需要小鼠模型的系统中研究蛋白质磷酸化。细胞周期蛋白E相关的肿瘤发生机制在很大程度上是未知的。该目标的总体目标是使用细胞周期蛋白E转基因和基因敲入菌株来开发细胞周期蛋白E相关癌症的模型。因为我们已经发现了一个稳态的p53依赖性反应,抑制过度的细胞周期蛋白E的活性,我们将专门测试的假设,p53功能的损失是一个不可分割的一步,在发展中的肿瘤与失调的细胞周期蛋白E的表达。这些模型将用于研究细胞周期蛋白E相关的肿瘤发生机制,并可能促进新的治疗策略的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bruce E Clurman其他文献
Cyclin E in normal and neoplastic cell cycles
正常和肿瘤细胞周期中的细胞周期蛋白 E
- DOI:
10.1038/sj.onc.1208613 - 发表时间:
2005-04-18 - 期刊:
- 影响因子:7.300
- 作者:
Harry C Hwang;Bruce E Clurman - 通讯作者:
Bruce E Clurman
Bruce E Clurman的其他文献
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{{ truncateString('Bruce E Clurman', 18)}}的其他基金
The Fbw7 ubiquitin ligase network: normal and neoplastic functions
Fbw7 泛素连接酶网络:正常和肿瘤功能
- 批准号:
10639893 - 财政年份:2023
- 资助金额:
$ 38.49万 - 项目类别:
Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer
利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法
- 批准号:
10171805 - 财政年份:2017
- 资助金额:
$ 38.49万 - 项目类别:
Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer
利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法
- 批准号:
9398810 - 财政年份:2017
- 资助金额:
$ 38.49万 - 项目类别:
Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer
利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法
- 批准号:
10603076 - 财政年份:2017
- 资助金额:
$ 38.49万 - 项目类别:
Identifying CDK4 and CDK6 substrates in cancers and cancer therapy
鉴定癌症和癌症治疗中的 CDK4 和 CDK6 底物
- 批准号:
8958740 - 财政年份:2015
- 资助金额:
$ 38.49万 - 项目类别:
Developing Ubiquitin Ligase Agonists as Cancer Therapeutics
开发泛素连接酶激动剂作为癌症治疗药物
- 批准号:
8562191 - 财政年份:2013
- 资助金额:
$ 38.49万 - 项目类别:
Cell Proliferation and Differentiation By the Fbw 7 Tumor Suppressor
Fbw 7 肿瘤抑制因子促进细胞增殖和分化
- 批准号:
7226081 - 财政年份:2006
- 资助金额:
$ 38.49万 - 项目类别:
Normal and Neoplastic Regulation of Cyclin E
细胞周期蛋白 E 的正常和肿瘤调节
- 批准号:
7253916 - 财政年份:2003
- 资助金额:
$ 38.49万 - 项目类别:
Normal and Neoplastic Regulation of Cyclin E
细胞周期蛋白 E 的正常和肿瘤调节
- 批准号:
7997178 - 财政年份:2003
- 资助金额:
$ 38.49万 - 项目类别:
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