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: 8034794
• 负责人: Anna Mandinova
• 金额: $ 30.85万
• 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/8034794
• 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; base; carcinogenesis; cell type; chemical carcinogenesis; in vivo; keratinocyte; loss of function; mouse model; notch protein; novel; programs; promoter; public health relevance; receptor; small molecule; therapeutic development; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: An aberrant signaling through the Notch1 receptor pathway is closely associated with various steps of carcinogenesis in the skin. Further understanding of the downstream molecular pathways and the target molecules, such as RhoE, responsible for the tumor suppression function of Notch1 in the epidermis is expected to eventually translate into therapeutic benefit in the treatment of non-melanoma skin cancer.

描述（由申请人提供）：虽然在大多数哺乳动物系统中，Notch活化通常被认为促进增殖并抑制分化，但在特定细胞类型如角质形成细胞中，Notch信号传导增加可能通过终末分化程序的启动导致生长停滞。此外，Notch 1缺陷型角质形成细胞对化学致癌作用敏感，从而确立了Notch作为表皮中的肿瘤生长抑制剂。我们最近发现了一种新的信号通路在角质形成细胞涉及抑制Notch 1基因下游的p53，这在鳞状细胞癌（SCC）的发展中起着关键作用。探索表皮中激活的Notch受体的下游效应，我们发现小的GTdR RhoE是Notch 1的新的转录靶点，其对于角质形成细胞中的分化开关是必需的。体外和体内RhoE缺乏使得角质形成细胞对Notch 1介导的分化诱导具有抗性，从而有利于不受控制的生长和增殖。此外，我们有强有力的证据表明，RhoE结合到激活的Notch 1和介导的Notch 1转录复合物的募集到其靶基因的启动子。我们的工作假设是，RhoE是Notch 1介导的分化和抑制表皮癌变/肿瘤发生的关键调节因子。我们将探讨这一新的Notch 1调控层RhoE在体外和体内角质形成细胞的分子机制。我们将详细剖析Notch 1-RhoE相互作用的功能，并将阐明其在体外和体内的RhoE基因敲除小鼠模型中的皮肤非黑色素瘤肿瘤发展的功能后果。对控制表皮中Notch-RhoE信号级联的途径的进一步机制理解预期最终转化为用于治疗皮肤SCC和具有下调的Notch信号传导的其他上皮恶性肿瘤的治疗剂的开发。 公共卫生关系：通过Notch 1受体途径的异常信号传导与皮肤中致癌的各个步骤密切相关。进一步了解下游分子途径和靶分子，如RhoE，负责Notch 1在表皮中的肿瘤抑制功能，预计最终将转化为治疗非黑色素瘤皮肤癌的治疗益处。