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

Role of a novel Notch1 target gene in skin carcinogenesis

新型Notch1靶基因在皮肤癌发生中的作用

基本信息

批准号：
8597529
负责人：
Anna Mandinova
金额：
$ 29.85万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597529
关键词：
Address Affect Binding Biochemical Biological Assay Cancer Cell Growth Cell Nucleus Complex Data Development Differentiation and Growth Epidermis Epithelial Gene Targeting Genes Genetic Transcription Growth Growth Inhibitors In Vitro Knockout Mice Malignant Epithelial Cell Malignant Neoplasms Mediating Mediator of activation protein Molecular Monomeric GTP-Binding Proteins Mus Mutant Strains Mice Pathway interactions Play Regulation Resistance Role Signal Pathway Signal Transduction Skin Skin Carcinogenesis Skin Carcinoma Squamous cell carcinoma Stream System TP53 gene Testing Therapeutic Transcriptional Regulation Translating Tumor Suppression Tumorigenicity Work abstracting base carcinogenesis cell type chemical carcinogenesis in vivo keratinocyte loss of function mouse model notch protein novel programs promoter receptor small molecule therapeutic development tumor tumor growth tumorigenesis

项目摘要

Abstract While in the majority of mammalian systems, Notch activation is generally thought to promote proliferation and inhibit differentiation, in specific cell types such as keratinocytes, increased Notch signaling results in growth arrest probably through initiation of terminal differentiation program. In addition, Notch1 deficient keratinocytes are sensitive to chemical carcinogenesis, establishing Notch as a tumor growth inhibitor in the epidermis. We have recently identified a novel signaling pathway in keratinocytes involving inhibition of the Notch1 gene downstream of p53, which plays a key role in squamous cell carcinoma (SCC) development. Exploring the downstream effects of activated Notch receptor in the epidermis, we found that the small GTPase RhoE is a new transcriptional target of Notch1, which is essential for the differentiation switch in keratinocytes. RhoE deficiency in vitro and in vivo renders keratinocytes resistant to Notch1-mediated induction of differentiation thereby favoring uncontrolled growth and proliferation. Furthermore, we have strong evidence that RhoE binds to activated Notch1 and mediates the recruitment of the Notch1-transcriptional complex to the promoters of its target genes. Our working hypothesis is that RhoE is a key regulator of Notch1-mediated commitment to differentiation and suppression of carcinogenesis/tumorigenesis in the epidermis. We will explore the molecular mechanism underlying this novel layer of Notch1 regulation by RhoE in keratinocytes in vitro and in vivo. We will dissect in details the functional Notch1-RhoE interaction and will elucidate its functional consequences for non-melanoma tumor development in the skin in vitro, as well as in vivo, in a RhoE knockout mouse model. Further mechanistic understanding of the pathway(s) controlling the Notch-RhoE signaling cascade in the epidermis is expected to eventually translate into the development of therapeutics for the treatment of skin SCCs and other epithelial malignancies with down-modulated Notch signaling.

摘要而在大多数哺乳动物系统中，Notch的激活通常被认为促进在特定类型的细胞中，如角质形成细胞，增殖和抑制分化增加缺口信号可能通过启动末端分化导致生长停滞程序。此外，Notch1缺陷的角质形成细胞对化学致癌很敏感。将Notch确立为表皮中的肿瘤生长抑制因子。我们最近发现了一种角质形成细胞中涉及抑制Notch1基因下游的新的信号通路 P53在鳞状细胞癌(SCC)的发生发展中起关键作用。探索下游激活的Notch受体在表皮中的作用，我们发现小的 GTP酶RhoE是Notch1的一个新的转录靶点，对分化是必不可少的在角质形成细胞中进行切换。体外和体内RhoE缺乏使角质形成细胞对 NOTCH1介导的诱导分化从而有利于不受控制的生长和扩散。此外，我们有强有力的证据表明，RhoE与激活的Notch1和介导Notch1-转录复合体对其靶标启动子的招募基因。我们的工作假设是，RhoE是Notch1介导的承诺的关键调节因子用于分化和抑制表皮的致癌/致瘤作用。我们会探讨RhoE调控Notch1这一新层的分子机制角质形成细胞在体外和体内。我们将详细分析功能Notch1-RhoE相互作用并将阐明其对皮肤非黑色素瘤发展的功能影响在体外和体内，在RhoE基因敲除小鼠模型中。进一步的机械性理解控制表皮Notch-RhoE信号级联的通路(S)有望最终转化为治疗皮肤鳞状细胞癌和 Notch信号下调的其他上皮性恶性肿瘤。