CYLD Regulation of Epidermal Growth and Neoplasia

CYLD 对表皮生长和肿瘤的调节

• 批准号: 7303632
• 负责人: Jennifer Yunyan Zhang
• 金额: $ 7.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7303632
• 关键词: Abnormal Cell; Adaptor Signaling Protein; Address; Adult; Alleles; Apoptosis; Biochemical; Biology; Birth; Cell Cycle Progression; Cell Proliferation; Cell Surface Receptors; Cells; Chemicals; Cutaneous; Data; Epithelial; Epithelial Neoplasms; Etiology; Gene Silencing; Goals; Growth; Homeostasis; Human; Hyperplasia; In Vitro; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Mus; Mutate; Mutation; Neoplasms; Oncogenes; Oncogenic; Other Genetics; Pathogenesis; Pathway interactions; Patients; Play; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Skin Tissue; Skin graft; Small Interfering RNA; Squamous cell carcinoma; Surface; Testing; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; Tumor Tissue; UV induced; Ubiquitination; appendage; base; cell growth; environmental change; genetic linkage; human tissue; in vivo; insight; keratinocyte; loss of function mutation; mutant; penis foreskin; prevent; promoter; response; retroviral-mediated; skin disorder; stress-activated protein kinase 1; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Recent studies have established a genetic linkage of cyld to both familial and sporadic neoplasms that mostly arise from the epidermal cells of skin appendages, as distinct from surface epidermal cells. CYLD acts as a deubiquitinase that inhibits self-ubiquitination of TRAF2/TRAF6 proteins, the key adaptor molecules mediating signal transduction from cell surface receptors, and thereby inhibit downstream signaling pathways, including NF-?B and JNK signaling cascades. A previously predicted role for the canonical NF-?B pathway in the etiology of skin neoplasms was recently challenged by findings revealing unaltered NF-KB RelA function in the TPA-induced hyperproliferation of cyld-/- mice epidermal cells. In addition, we have recently demonstrated that NF-?B is crucial in epidermal growth control and its blockade contributes to squamous cell carcinoma (SCC) in a JNK/AP1 function dependent manner. These finding lead us to hypothesize that CYLD inhibition acts through JNK cascade to promote neoplasia. The first goal of this study is to define the mechanisms of CYLD regulation of epidermal cell growth and to explore whether the JNK signaling cascade play a central role in CYLD effects on epidermal homeostasis. To do this, we will isolate multiple types of primary human epidermal cells from surgically disposed foreskin or adult skin and study their growth response to genetically modified CYLD function, as well as JNK signaling. The second goal is to study CYLD-driven neoplasia in vivo by generating both mice and human transgenic skin tissue. We will investigate whether inhibiting or augmenting NF-?B, JNK or Ras-MAPK signaling cascades will prevent or potentiate CYLD induced neoplasia. By the end of this proposal, we hope to have determined the mechanism of CYLD regulation of epidermal homeostasis and cutaneous epithelial neoplasms. This effort is based on the premise that characterizing the molecular mechanisms in CYLDmediated cell growth and neoplasia in skin tissue will both provide new insights into basic epithelial biology as well as characterize therapeutic targets for human skin diseases.

描述(由申请人提供)： 最近的研究已经建立了CYLD与家族性和散发性肿瘤的遗传联系，这些肿瘤大多起源于皮肤附件的表皮细胞，与表面表皮细胞不同。CyLD是一种去泛素酶，它抑制TRAF2/TRAF6蛋白的自身泛素化，而TRAF2/TRAF6蛋白是介导细胞表面受体信号转导的关键适配分子，从而抑制下游信号通路，包括核因子-β和JNK信号通路。最近发现，在TPA诱导的CyLD-/-小鼠表皮细胞过度增殖中，核因子-kB RelA的功能没有改变，这对先前预测的典型的核因子-？B途径在皮肤肿瘤病因学中的作用提出了挑战。此外，我们最近证明了核因子-β在表皮生长控制中起关键作用，它的阻断以JNK/AP1功能依赖的方式促进鳞状细胞癌(SCC)的发生。这些发现使我们假设，CyLD抑制通过JNK级联作用促进肿瘤发生。本研究的第一个目的是明确CyLD对表皮细胞生长的调控机制，并探讨JNK信号通路是否在CyLD对表皮内环境的影响中起核心作用。为此，我们将从手术处理的包皮或成人皮肤中分离出多种类型的原代人类表皮细胞，并研究它们对基因修饰的CyLD功能以及JNK信号的生长反应。第二个目标是通过产生小鼠和人类转基因皮肤组织，在体内研究CyLD驱动的肿瘤。我们将研究抑制或增强NF-B、JNK或Ras-MAPK信号转导通路是否能预防或加强CyLD诱导的肿瘤发生。最后，我们希望能够确定CyLD对表皮动态平衡和皮肤上皮性肿瘤的调节机制。这项工作的前提是，表征CyLDs介导的细胞生长和皮肤组织肿瘤的分子机制将为基础上皮生物学提供新的见解，并确定人类皮肤病的治疗靶点。