Regulation of ER-nuclear communication by CREB3 transmembrane transcription factors
CREB3跨膜转录因子对内质网核通讯的调节
基本信息
- 批准号:MR/K017926/1
- 负责人:
- 金额:$ 42.69万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2013
- 资助国家:英国
- 起止时间:2013 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Our cells carry out a broad range of functions, some of which are common and some distinct for each cell type. As examples, certain cells in our pancreas sense metabolic signals and regulate secretion of insulin to control variations in blood glucose. Different cells in the pancreas play a role in the secretion of enzymes that help breakdown ingested foodstuffs. Cells within developing bone secrete components that build bone matrix, while cells of our blood system produce and secrete antibodies to combat infection. These particular examples reflect a common critical function with which this application is concerned, namely the proper control of secretion and secretory function. The secretory pathway is controlled by a specialized apparatus, termed the endoplasmic reticulum (ER). This coordinated network of membrane-bound organelles is ultimately responsible for the general and cell-type specific secretion of all the proteins and other components that carry out the diverse functions in the examples above. Therefore, malfunction of ER pathways is associated with a wide range of important human diseases. Examples include diabetes and lipid disorders, conditions associated with defective bone formation, and diseases associated with malfunction in secretion and inflammation in the intestine such as ulcerative coilitis. Although the links with human disease are well established, many aspects of the detailed mechanisms regulating ER functions and their role in normal processes and disease progression remain poorly understood. A general feature of cellular function is the process of homeostasis, i.e. the regulation of internal conditions by a system of feedback controls to stabilize the health and proper functioning of the cell in response to changing conditions. This process frequently involves the control of gene expression. A specialized homeostatic pathway occurs in the ER for the control of cholesterol levels in our bodies. In this pathway a transcription factor is physically associated with the ER, where it senses alterations in cholesterol, and as a result is processed and transported to the nucleus to stimulate cholesterol production. Knowledge of this pathway has contributed significantly to understanding cholesterol balance and imbalance in health and disease.Through our work, we now know there are additional factors, called CREB3 proteins, that are also physically anchored in the ER and control adaptive responses by relaying information back to the nucleus. Recent work has demonstrated that they play vital functions at the ER and are required, for example, in developing bone cells, for normal cartilage formation, and in liver for the control of secreted fatty acid and triglyceride levels. However we have very little mechanistic understanding of how they function. The principle aims of this proposal are to understand the detailed mechanisms controlling CREB3 activity and how they regulate these distinct downstream pathways. We will address two main objectives; firstly understanding the signalling pathways that control how these factors are retained in the ER and how they are released and transported to the nucleus; secondly, what proteins they interact with to dictate cellular localisation Overall, elucidation of the mechanisms controlling CREB3 proteins and their transcriptional regulation of adaptive responses will contribute significantly to our understanding of ER biology and important physiological pathways and potentially yield new insight into disease processes of significant burden in the population. Understanding their role and function may also have application e.g., in manipulating the secretory pathway to increase production of desired products.
我们的细胞执行广泛的功能,其中一些是共同的,有些是不同的细胞类型。例如,我们胰腺中的某些细胞感知代谢信号并调节胰岛素的分泌来控制血糖的变化。胰腺中不同的细胞在酶的分泌中发挥作用,帮助分解摄入的食物。发育中的骨细胞分泌组成骨基质的成分,而我们血液系统的细胞产生和分泌抗体来对抗感染。这些特殊的例子反映了这一应用所涉及的一个共同的关键功能,即对分泌和分泌功能的适当控制。分泌途径由一种称为内质网(ER)的特殊装置控制。这种膜结合细胞器的协调网络最终负责所有蛋白质和其他成分的一般和细胞类型特异性分泌,这些蛋白质和其他成分在上面的例子中执行各种功能。因此,内质网通路的功能障碍与一系列重要的人类疾病有关。例子包括糖尿病和脂质紊乱,与骨形成缺陷相关的疾病,以及与分泌功能障碍和肠道炎症相关的疾病,如溃疡性结肠炎。尽管内质网与人类疾病的联系已被证实,但内质网功能的详细调节机制的许多方面及其在正常过程和疾病进展中的作用仍知之甚少。细胞功能的一个普遍特征是体内平衡过程,即通过反馈控制系统调节内部条件,以稳定细胞的健康和正常功能,以应对不断变化的条件。这个过程经常涉及到基因表达的控制。内质网中有一种特殊的体内平衡途径来控制我们体内的胆固醇水平。在这一途径中,转录因子与内质网发生物理联系,在内质网感知胆固醇的变化,并因此被加工和运输到细胞核以刺激胆固醇的产生。这一途径的知识对理解健康和疾病中的胆固醇平衡和不平衡有重要贡献。通过我们的工作,我们现在知道还有其他的因子,称为CREB3蛋白,它们也物理地固定在内质网中,并通过将信息传递回细胞核来控制适应性反应。最近的研究表明,它们在内质网中起着至关重要的作用,例如,在骨细胞的发育、正常软骨的形成以及肝脏中控制分泌脂肪酸和甘油三酯水平的过程中都是必需的。然而,我们对它们的作用机制知之甚少。本提案的主要目的是了解控制CREB3活性的详细机制以及它们如何调节这些不同的下游途径。我们将处理两个主要目标;首先了解控制这些因子如何在内质网中保留以及它们如何被释放和运输到细胞核的信号通路;其次,它们与哪些蛋白质相互作用来决定细胞定位。总的来说,阐明CREB3蛋白的控制机制及其对适应性反应的转录调控将有助于我们对内质网生物学和重要生理途径的理解,并可能对人群中重大负担的疾病过程产生新的见解。了解它们的作用和功能也可能有应用,例如,在操纵分泌途径,以增加所需产品的生产。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phosphorylation and SCF-mediated degradation regulate CREB-H transcription of metabolic targets.
- DOI:10.1091/mbc.e15-04-0247
- 发表时间:2015-08-15
- 期刊:
- 影响因子:3.3
- 作者:Barbosa S;Carreira S;Bailey D;Abaitua F;O'Hare P
- 通讯作者:O'Hare P
An orchestrated program regulating secretory pathway genes and cargos by the transmembrane transcription factor CREB-H.
- DOI:10.1111/tra.12038
- 发表时间:2013-04
- 期刊:
- 影响因子:0
- 作者:Barbosa S;Fasanella G;Carreira S;Llarena M;Fox R;Barreca C;Andrew D;O'Hare P
- 通讯作者:O'Hare P
GSK-3-mediated phosphorylation couples ER-Golgi transport and nuclear stabilization of the CREB-H transcription factor to mediate apolipoprotein secretion.
- DOI:10.1091/mbc.e17-01-0075
- 发表时间:2017-06-01
- 期刊:
- 影响因子:3.3
- 作者:Barbosa S;Carreira S;O'Hare P
- 通讯作者:O'Hare P
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Peter O'Hare其他文献
Lower Serum AMH Levels are Associated with Longer Gonadotropin Stimulations
- DOI:
10.1016/j.genm.2011.09.013 - 发表时间:
2012-02-01 - 期刊:
- 影响因子:
- 作者:
Peter O'Hare - 通讯作者:
Peter O'Hare
Peter O'Hare的其他文献
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{{ truncateString('Peter O'Hare', 18)}}的其他基金
A systems approach to elucidation of protein lipidation during virus infection
阐明病毒感染过程中蛋白质脂化的系统方法
- 批准号:
MR/L000148/1 - 财政年份:2013
- 资助金额:
$ 42.69万 - 项目类别:
Research Grant
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