Role of a novel Notch1 target gene in skin carcinogenesis

描述(申请人提供)：虽然在大多数哺乳动物系统中，Notch的激活通常被认为促进增殖和抑制分化，但在特定类型的细胞，如角质形成细胞中，Notch信号的增加可能通过启动末端分化程序导致生长停滞。此外，Notch1缺陷的角质形成细胞对化学致癌非常敏感，这使得Notch成为表皮中的一种肿瘤生长抑制因子。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，它在鳞状细胞癌(SCC)的发展中起着关键作用。通过探索激活的Notch受体在表皮中的下游作用，我们发现小GTPase RhoE是Notch1的一个新的转录靶点，它是角质形成细胞分化开关所必需的。在体外和体内，RhoE缺乏使角质形成细胞抵抗Notch1介导的诱导分化，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-转录复合体向其靶基因启动子的招募。我们的工作假设是，RhoE是Notch1介导的致力于分化和抑制表皮癌变/肿瘤发生的关键调节因子。我们将在体外和体内探索RhoE在角质形成细胞中调控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，并阐明其在体外皮肤和体内RhoE基因敲除小鼠模型中对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(S)的进一步机械理解有望最终转化为治疗皮肤SCC和其他具有下调Notch信号的上皮性恶性肿瘤的治疗方法的发展。 公共卫生相关性：通过Notch1受体通路的异常信号与皮肤致癌的各个步骤密切相关。进一步了解下游分子通路和靶分子，如RhoE，负责表皮Notch1的肿瘤抑制功能，有望最终转化为治疗非黑色素瘤皮肤癌的益处。

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.