Characterisation of a new mechanism of regulation for HIF1 and the hypoxic response.

HIF1 和缺氧反应的新调节机制的表征。

• 批准号: BB/L027755/1
• 负责人: Tyson Sharp
• 金额: $ 42.72万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL027755%2F1
• 关键词: Characterisation; new; mechanism; regulation; HIF1

I believe our track record with the BBSRC and our publications demonstrate we can achieve the goals of this exciting project and successfully return this grant with novel and significant insights and advances to LIMD1 biology and the HIF signalling pathway.Optimum levels of oxygen are required throughout the cells and tissues of our body for survival. Referred to as 'oxygen homeostasis', this is tightly regulated in animals and indeed all multicellular organisms to ensure that tissues are sufficiently supplied with oxygen. Whilst oxygen levels range within the human body from 21% in the upper airway to an average of 5% in most organs, each tissue type has a requirement for a certain concentration of oxygen, below which essential cellular processes such as energy production, protein synthesis and cell growth and division become impaired. Rapid reaction and adaptation of a cell or tissue to low oxygen concentrations ('hypoxia') can enable cells to remain viable, thus reducing potential damage to the organism. This is known as the 'hypoxic response'. Deregulation of the hypoxic response is a key characteristic in cancer development and also large tumour growth and its spread throughout the body. Furthermore, deregulation of this key cellular control process is also linked to many non-cancerous diseases such as neurological disease, myocardial infarction (heart attacks), stokes, and many ischemic (low oxygen) related diseases. Therefore, a complete understanding of the molecular biology of this critical cellular control process remains an important focus for basic cell and molecular biology research worldwide. To this end we have recently identified a protein called LIMD1 that is a critical to regulating the normal function of the hypoxic response. Furthermore, we have shown that loss of this protein creates a pseudo-hypoxic environment within the cell, causing it to react as if it is in one of the hypoxic diseased states mentioned above. Our discovery therefore represents a new unknown level of molecular biology critical for the hypoxic response. Moreover, we are currently the only group in the world to be researching this specific area of hypoxic regulation, and hopefully with this BBSRC award, we can continue to investigate this exciting new molecular biology. Furthermore, such information will represent a major new avenue of investigation to basic and clinical molecular biological researchers in this field and represent a new set of protein targets for future development of hypoxic disease-related drug therapies and treatments.

我相信，我们与BBSRC的记录和我们的出版物表明，我们可以实现这个令人兴奋的项目的目标，并成功地以LIMD1生物学和HIF信号通路的新颖和重要的见解和进展回报这笔资助。为了生存，我们身体的细胞和组织都需要最佳水平的氧气。这被称为“氧稳态”，在动物和所有多细胞生物中受到严格调节，以确保组织获得足够的氧气供应。虽然人体内的氧气含量从上呼吸道的21%到大多数器官的平均5%不等，但每种组织类型都需要一定浓度的氧气，低于这个浓度，能量产生、蛋白质合成和细胞生长和分裂等基本细胞过程就会受到损害。细胞或组织对低氧浓度（“缺氧”）的快速反应和适应可以使细胞保持活力，从而减少对生物体的潜在损害。这就是所谓的“缺氧反应”。缺氧反应的解除是癌症发展的关键特征，也是大肿瘤生长和全身扩散的关键特征。此外，这一关键细胞控制过程的解除也与许多非癌性疾病有关，如神经系统疾病、心肌梗死（心脏病发作）、中风和许多缺血性（低氧）相关疾病。因此，全面了解这一关键细胞调控过程的分子生物学仍然是世界范围内基础细胞和分子生物学研究的重要焦点。为此，我们最近发现了一种名为LIMD1的蛋白质，它对调节缺氧反应的正常功能至关重要。此外，我们已经证明，这种蛋白质的缺失会在细胞内产生一种伪缺氧环境，导致细胞的反应就像上面提到的一种缺氧疾病状态。因此，我们的发现代表了对缺氧反应至关重要的分子生物学的一个新的未知水平。此外，我们是目前世界上唯一一个研究缺氧调节这一特定领域的团队，希望有了BBSRC奖，我们可以继续研究这一令人兴奋的新分子生物学。此外，这些信息将为该领域的基础和临床分子生物学研究人员提供一条重要的新研究途径，并为未来开发与缺氧疾病相关的药物治疗和治疗提供一套新的蛋白质靶点。

项目成果

CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.

• DOI: 10.1158/0008-5472.can-15-3134
• 发表时间: 2016-08-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Feber A;Worth DC;Chakravarthy A;de Winter P;Shah K;Arya M;Saqib M;Nigam R;Malone PR;Tan WS;Rodney S;Freeman A;Jameson C;Wilson GA;Powles T;Beck S;Fenton T;Sharp TV;Muneer A;Kelly JD
• 通讯作者: Kelly JD

Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition.

• DOI: 10.1038/onc.2016.435
• 发表时间: 2017-05-11
• 期刊: Oncogene
• 影响因子: 8
• 作者: Dermit M;Casado P;Rajeeve V;Wilkes EH;Foxler DE;Campbell H;Critchlow S;Sharp TV;Gribben JG;Unwin R;Cutillas PR
• 通讯作者: Cutillas PR

Suppression of AGO2 by miR-132 as a determinant of miRNA-mediated silencing in human primary endothelial cells.

• DOI: 10.1016/j.biocel.2015.10.006
• 发表时间: 2015-12
• 期刊: The international journal of biochemistry & cell biology
• 作者: Leonov G;Shah K;Yee D;Timmis J;Sharp TV;Lagos D
• 通讯作者: Lagos D

Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.

• DOI: 10.1016/j.celrep.2017.06.027
• 发表时间: 2017-07-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Bridge KS;Shah KM;Li Y;Foxler DE;Wong SCK;Miller DC;Davidson KM;Foster JG;Rose R;Hodgkinson MR;Ribeiro PS;Aboobaker AA;Yashiro K;Wang X;Graves PR;Plevin MJ;Lagos D;Sharp TV
• 通讯作者: Sharp TV

A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.

• DOI: 10.15252/emmm.201708304
• 发表时间: 2018-08
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Foxler DE;Bridge KS;Foster JG;Grevitt P;Curry S;Shah KM;Davidson KM;Nagano A;Gadaleta E;Rhys HI;Kennedy PT;Hermida MA;Chang TY;Shaw PE;Reynolds LE;McKay TR;Wang HW;Ribeiro PS;Plevin MJ;Lagos D;Lemoine NR;Rajan P;Graham TA;Chelala C;Hodivala-Dilke KM;Spendlove I;Sharp TV
• 通讯作者: Sharp TV