Role of a novel Notch1 target gene in skin carcinogenesis

描述（由申请人提供）：虽然在大多数哺乳动物系统中，Notch激活通常被认为促进增殖和抑制分化，但在特定细胞类型（如角质形成细胞）中，Notch信号的增加可能通过启动终端分化程序导致生长停滞。此外，Notch1缺失的角质形成细胞对化学癌变敏感，这表明Notch在表皮中是肿瘤生长抑制剂。我们最近在角质形成细胞中发现了一个新的信号通路，涉及抑制p53下游的Notch1基因，该基因在鳞状细胞癌（SCC）的发展中起关键作用。通过对激活Notch受体在表皮中的下游作用的探索，我们发现小GTPase RhoE是Notch1的一个新的转录靶点，Notch1在角化细胞的分化开关中起着至关重要的作用。体外和体内RhoE缺乏使角质形成细胞对notch1介导的诱导分化产生抗性，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与激活的Notch1结合，并介导Notch1转录复合物募集到其靶基因的启动子上。我们的工作假设是，RhoE是notch1介导的表皮分化和抑制致癌/肿瘤发生的关键调节因子。我们将在体外和体内研究角化细胞中RhoE调控Notch1这一新层的分子机制。我们将详细剖析Notch1-RhoE的功能相互作用，并阐明其在体外和体内RhoE敲除小鼠模型中对皮肤非黑色素瘤肿瘤发展的功能影响。对控制表皮Notch- rhoe信号级联通路的进一步机制理解有望最终转化为治疗皮肤SCCs和其他Notch信号下调的上皮恶性肿瘤的治疗方法的开发。

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.