权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of the oncogenic potential of signalling through the Ras/ERK pathway by dual-specificity phosphatase 5

双特异性磷酸酶 5 通过 Ras/ERK 途径调节信号传导的致癌潜力

基本信息

批准号：
MR/N020790/1
负责人：
Stephen Keyse
金额：
$ 75.84万
依托单位：
University of Dundee
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN020790%2F1
关键词：
Regulation oncogenic potential signalling through

项目摘要

Abnormal activation of the Ras/ERK signalling pathway plays a causative role in disease initiation and progression and approximately one third of all human cancers exhibit mutations known to cause Ras/ERK mediated cancer formation. Furthermore, many of these cancers, such as pancreatic cancer, lung cancer and malignant melanoma have few treatment options and a poor prognosis, making this pathway an intense focus of anticancer drug development. We understand a lot about how activating mutations in ERK pathway components, such as Ras or its downstream target, Braf, cause ERK signalling to be uncontrollably "switched on" in tumours, and that such mutations can determine tumour sensitivity to anticancer drugs that inhibit the Ras/ERK pathway. In contrast, we know little about how the negative regulators of Ras/ERK signalling influence oncogenesis or drug sensitivity.We recently demonstrated that DUSP5, an inducible protein phosphatase, inhibits nuclear Ras/ERK activity and gene expression, and that deletion of DUSP5 dramatically increases mutant Ras-induced skin tumour burdens in mice, demonstrating that DUSP5 is a tumour suppressor. We therefore hypothesise that DUSP5 limits the progression of mutant Ras tumours in other tissues and in human tumours. In contrast, our more recent studies using cultured cells indicate that in the presence of Braf mutations, DUSP5 actually promotes cell growth and its deletion halts cell proliferation. We therefore hypothesise that, much like their effect on some anticancer drugs, the presence of Ras or Braf oncogenes can determine whether DUSP5 promotes or suppresses cancer cell growth. The overall objectives of this research project are two-fold:1) We will determine the effects of DUSP5 loss in clinically relevant mouse models of mutant Kras-induced cancer, namely pancreatic and lung carcinogenesis. These models closely resemble the human disease and will enable us to assess the role of DUSP5 in modulating the initiation and progression of tumours. This will be coupled with a detailed analysis of changes in ERK-dependent gene expression and signalling endpoints associated with cell proliferation, senescence, survival, migration and cell death. The latter will allow us to identify mechanism(s) and also key targets of ERK signalling involved in promoting tumour development. Finally, we will screen normal and tumour tissue samples from pancreatic cancer patients in order to assess the levels of DUSP5 and other key ERK signalling targets and to explore correlations with clinical endpoints in human disease.2) We will determine whether the role of DUSP5 in modulating the oncogenic effects of Ras/ERK signalling depends on the way in which the pathway is activated. This will be studied by monitoring the influence of DUSP5 on ERK signalling and cell fate in the presence of either Ras or Braf mutations. This has important implications for predicting how effective Ras/ERK pathway inhibitors may be in the treatment of cancer. We will therefore study the molecular mechanisms which underpin this functional difference and extend these studies to cancer cell lines in which Ras or Braf are mutant and determine if DUSP5 expression affects sensitivity either acute or chronic exposure to Ras/ERK inhibitors in clinical use. Overall, this work will inform us about DUSP5 function in the regulation of Ras/ERK signalling as it relates to cancer initiation and development, will shed light on the relative importance of the Ras/ERK pathway and its targets in cancers driven by mutant Kras and allow us to explore their clinical relevance. Finally, the idea that the role of DUSP5 in regulating ERK may become more important in the presence of activating oncogenes represents an unexplored area in terms of cellular responses to pathway inhibitors and may open new approaches to modulating or predicting patient responses to drugs which target Ras/ERK signalling in cancer.

Ras/ERK信号通路的异常激活在疾病的起始和进展中起着致病作用，并且大约三分之一的人类癌症表现出已知引起Ras/ERK介导的癌症形成的突变。此外，许多这些癌症，如胰腺癌，肺癌和恶性黑色素瘤的治疗选择很少，预后差，使这一途径成为抗癌药物开发的重点。我们了解了很多关于ERK通路组分（如Ras或其下游靶点Braf）中的激活突变如何导致ERK信号在肿瘤中不受控制地“打开”，并且这些突变可以决定肿瘤对抑制Ras/ERK通路的抗癌药物的敏感性。相比之下，我们知道的Ras/ERK信号的负调控如何影响肿瘤发生或药物sensitivity.We最近证明，DUSP 5，诱导蛋白磷酸酶，抑制核Ras/ERK活性和基因表达，并删除DUSP 5显着增加突变Ras诱导的小鼠皮肤肿瘤的负担，表明DUSP 5是一种肿瘤抑制因子。因此，我们假设DUSP 5限制了突变型Ras肿瘤在其他组织和人类肿瘤中的进展。相比之下，我们最近使用培养细胞的研究表明，在存在Braf突变的情况下，DUSP 5实际上促进细胞生长，其缺失会阻止细胞增殖。因此，我们假设，就像它们对某些抗癌药物的作用一样，Ras或Braf癌基因的存在可以决定DUSP 5是促进还是抑制癌细胞生长。本研究项目的总体目标有两个方面：1）我们将确定DUSP 5缺失在突变型Kras诱导的癌症（即胰腺癌和肺癌）的临床相关小鼠模型中的影响。这些模型与人类疾病非常相似，将使我们能够评估DUSP 5在调节肿瘤发生和发展中的作用。这将与ERK依赖性基因表达和与细胞增殖，衰老，存活，迁移和细胞死亡相关的信号传导终点的变化的详细分析相结合。后者将使我们能够确定参与促进肿瘤发展的ERK信号传导的机制和关键靶点。最后，我们将筛选胰腺癌患者的正常和肿瘤组织样本，以评估DUSP 5和其他关键ERK信号传导靶点的水平，并探索与人类疾病临床终点的相关性。2）我们将确定DUSP 5在调节Ras/ERK信号传导的致癌作用中的作用是否取决于该途径被激活的方式。这将通过监测Ras或Braf突变存在时DUSP 5对ERK信号传导和细胞命运的影响来研究。这对于预测Ras/ERK通路抑制剂在癌症治疗中的有效性具有重要意义。因此，我们将研究支持这种功能差异的分子机制，并将这些研究扩展到Ras或Braf突变的癌细胞系，并确定DUSP 5表达是否影响临床使用中急性或慢性暴露于Ras/ERK抑制剂的敏感性。总的来说，这项工作将告诉我们DUSP 5在调节Ras/ERK信号传导中的功能，因为它与癌症的发生和发展有关，将阐明Ras/ERK通路及其靶点在突变Kras驱动的癌症中的相对重要性，并使我们能够探索其临床相关性。最后，DUSP 5在调节ERK中的作用在活化癌基因的存在下可能变得更加重要的想法代表了细胞对通路抑制剂的反应方面的未探索领域，并且可能开辟新的方法来调节或预测患者对靶向癌症中Ras/ERK信号传导的药物的反应。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy.

DOI：
10.1152/ajpheart.00115.2021
发表时间：
2021-08-01
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Ferguson BS;Wennersten SA;Demos-Davies KM;Rubino M;Robinson EL;Cavasin MA;Stratton MS;Kidger AM;Hu T;Keyse SM;McKnight RA;Lane RH;Nozik ES;Weiser-Evans MCM;McKinsey TA
通讯作者：
McKinsey TA

Dual-specificity MAP kinase phosphatases in health and disease.