The Ccr4-Not Complex: Bifunctional roles in Repression of Steroid Receptor-Mediated Transcription and mRNA Decay?

Ccr4-Not 复合物:在抑制类固醇受体介导的转录和 mRNA 衰变中的双功能作用?

基本信息

  • 批准号:
    BB/E02338X/1
  • 负责人:
  • 金额:
    $ 38.85万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2007
  • 资助国家:
    英国
  • 起止时间:
    2007 至 无数据
  • 项目状态:
    已结题

项目摘要

Cells can respond to environmental factors such as hormones by changing the instructions that are used. These instructions, or genes, are contained in the heritable material, the DNA. When genes are actively expressed, mRNA copies are produced by transcription in some, but not all cells. At a given time, only a sub-set of genes is expressed by a highly regulated and complex process that requires thousands of different protein factors. The precise number of factors involved in transcription is unknown, and the mechanism by which they work is often unclear. Because different cells contain different transcription factors, a characteristic pattern of genes is expressed for each cell type in the human body. Equally important to the activation of transcription, is the switching off of genes. This can be achieved in different manners. For example, factors can bind to DNA and repress transcription. Alternatively, factors can inactivate gene expression by destroying the mRNA copies of genes. The Ccr4-Not factor can potentially influence gene expression in both ways: by repressing transcription and by destruction of mRNA. Recently, we showed that this factor can interact with estrogen receptor. Estrogen receptor is a transcription factor that mediates the cellular effects of the steroid hormone estrogen. Binding of the hormone to estrogen receptor causes a structural change of the receptor which leads to activation of the receptor. As a result, the expression of several hundreds of genes is altered. Some genes are switched on and are actively transcribed in response to the hormone, such as several genes that promote cell division. Other genes are switched off in response and become repressed, including genes that inhibit cell division. The proposed work will investigate how Ccr4-Not will influence cellular gene expression in response to estrogen. It will do so by specifically engineer cells that lack subunits of Ccr4-Not. Using DNA microarray technology, the expression of >30,000 genes, the majority of human genes, will be determined in a single experiment. The resulting large data sets obtained using normal cells and cells lacking functional Ccr4-Not will be compared using bioinformatics. This will allow to define how important Ccr4-Not is in the cellular response to estrogen. In addition, the proposed work will determine to what extent Ccr4-Not uses its capacities to inhibit transcription and destroy mRNA to influence gene expression in response to estrogens. This will be done in cell lines that lack either the transcriptional repression function, or the mRNA destruction function of Ccr4-Not. Finally, because it is known that estrogens can stimulate cell proliferation, it will assess how Ccr4-Not can have an effect on cell division. The results will increase our basic understanding of the molecular machinery in cells. Furthermore, they may be of interest to the pharmaceutical industry, because there are several drugs that can bind to estrogen receptor and influence its activity in different ways as compared to the natural hormone estrogen. These drugs are successfully used for the treatment of osteoporosis, severe post-menopausal symptoms and cancer, but concerns about efficacy and safety remain. A better understanding of the workings of estrogen receptor may eventually result in the development of safer drugs.
细胞可以通过改变所使用的指令来响应环境因素,如激素。这些指令或基因包含在可遗传的物质DNA中。当基因被活跃地表达时,mRNA拷贝在一些但不是所有细胞中通过转录产生。在给定的时间,只有一个基因的子集是由一个高度调控和复杂的过程,需要数千种不同的蛋白质因子表达。参与转录的因子的确切数量是未知的,它们的工作机制也常常不清楚。由于不同的细胞含有不同的转录因子,因此人体中每种细胞类型都表达一种特征性的基因模式。与转录激活同样重要的是基因的关闭。这可以以不同的方式实现。例如,因子可以与DNA结合并抑制转录。或者,因子可以通过破坏基因的mRNA拷贝来抑制基因表达。Ccr 4-Not因子可能以两种方式影响基因表达:通过抑制转录和破坏mRNA。最近,我们发现该因子可以与雌激素受体相互作用。雌激素受体是一种转录因子,介导类固醇激素雌激素的细胞效应。激素与雌激素受体的结合引起受体的结构变化,这导致受体的活化。结果,数百个基因的表达被改变。一些基因被打开并积极转录以响应激素,例如促进细胞分裂的几个基因。其他基因在反应中被关闭并受到抑制,包括抑制细胞分裂的基因。拟议的工作将研究Ccr 4-Not如何影响细胞基因表达对雌激素的反应。它将通过专门设计缺乏Ccr 4-Not亚基的细胞来做到这一点。使用DNA微阵列技术,将在一次实验中确定超过30,000个基因(大多数人类基因)的表达。使用正常细胞和缺乏功能性Ccr 4-Not的细胞获得的所得大数据集将使用生物信息学进行比较。这将允许定义Ccr 4-Not在细胞对雌激素的反应中的重要性。此外,拟议的工作将确定Ccr 4-Not在多大程度上利用其抑制转录和破坏mRNA的能力来影响雌激素反应的基因表达。这将在缺乏Ccr 4-Not的转录抑制功能或mRNA破坏功能的细胞系中进行。最后,由于已知雌激素可以刺激细胞增殖,因此将评估Ccr 4-Not如何对细胞分裂产生影响。这些结果将增加我们对细胞分子机制的基本理解。此外,它们可能对制药工业感兴趣,因为与天然激素雌激素相比,有几种药物可以与雌激素受体结合并以不同的方式影响其活性。这些药物已成功用于治疗骨质疏松症、严重的绝经后症状和癌症,但对疗效和安全性的担忧仍然存在。更好地了解雌激素受体的作用可能最终导致更安全的药物的开发。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of eukaryotic mRNA deadenylation and degradation by the Ccr4-Not complex.
The anti-proliferative activity of BTG/TOB proteins is mediated via the Caf1a (CNOT7) and Caf1b (CNOT8) deadenylase subunits of the Ccr4-not complex.
  • DOI:
    10.1371/journal.pone.0051331
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Doidge R;Mittal S;Aslam A;Winkler GS
  • 通讯作者:
    Winkler GS
A non-proteolytic role for ubiquitin in deadenylation of MHC-I mRNA by the RNA-binding E3-ligase MEX-3C.
  • DOI:
    10.1038/ncomms9670
  • 发表时间:
    2015-10-16
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Cano F;Rapiteanu R;Sebastiaan Winkler G;Lehner PJ
  • 通讯作者:
    Lehner PJ
The Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the human Ccr4-Not complex contribute to the prevention of cell death and senescence.
  • DOI:
    10.1091/mbc.e10-11-0898
  • 发表时间:
    2011-03-15
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Mittal S;Aslam A;Doidge R;Medica R;Winkler GS
  • 通讯作者:
    Winkler GS
Post-transcriptional Control of Tumor Cell Autonomous Metastatic Potential by CCR4-NOT Deadenylase CNOT7.
  • DOI:
    10.1371/journal.pgen.1005820
  • 发表时间:
    2016-01
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Faraji F;Hu Y;Yang HH;Lee MP;Winkler GS;Hafner M;Hunter KW
  • 通讯作者:
    Hunter KW
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Gerlof Winkler其他文献

Gerlof Winkler的其他文献

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{{ truncateString('Gerlof Winkler', 18)}}的其他基金

Deadenylase enzymes as potential novel drug targets in osteoporosis, bone disease, and repair
脱腺苷酶作为骨质疏松症、骨疾病和修复的潜在新药物靶点
  • 批准号:
    G1100205/1
  • 财政年份:
    2011
  • 资助金额:
    $ 38.85万
  • 项目类别:
    Research Grant

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