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

• 批准号: 8204559
• 负责人: Anna Mandinova
• 金额: $ 30.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204559
• 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

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 虽然在大多数哺乳动物系统中，Notch激活通常被认为促进了细胞的增殖。 增殖和抑制分化，在特定的细胞类型，如角质形成细胞，增加 Notch信号可能通过启动终末分化导致生长停滞 程序.此外，Notch 1缺陷型角质形成细胞对化学致癌作用敏感， 建立Notch作为表皮中的肿瘤生长抑制剂。我们最近发现了一个 角质形成细胞中涉及抑制Notch 1基因下游的新信号传导途径 p53在鳞状细胞癌（SCC）的发生发展中起关键作用。探索 在表皮中激活的Notch受体的下游效应，我们发现， GTTR RhoE是Notch 1的一个新的转录靶点，它在细胞分化中起重要作用 角质形成细胞中的开关。RhoE在体外和体内的缺乏使得角质形成细胞对 Notch 1介导的分化诱导，从而有利于不受控制的生长， 增殖此外，我们有强有力的证据表明，RhoE结合活化的Notch 1， 介导Notch 1-转录复合物向其靶基因启动子的募集 基因.我们的工作假设是RhoE是Notch 1介导的承诺的关键调节因子 分化和抑制表皮中的癌发生/肿瘤发生。我们将 探索RhoE对Notch 1调控的这一新层的分子机制， 角质形成细胞在体外和体内。我们将详细剖析Notch 1-RhoE相互作用的功能 并将阐明其对皮肤中非黑色素瘤肿瘤发展的功能后果 体外以及体内，在RhoE敲除小鼠模型中。进一步的机械理解 预期控制表皮中Notch-RhoE信号级联的途径的 最终转化为治疗皮肤SCC的治疗剂的开发， 其他具有下调Notch信号传导的上皮恶性肿瘤。