CYLD Regulation of Epidermal Growth and Neoplasia

CYLD 对表皮生长和肿瘤的调节

基本信息

批准号：
7477788
负责人：
Jennifer Yunyan Zhang
金额：
$ 7.64万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7477788
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

项目摘要

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，这些肿瘤主要起源于皮肤附属器的表皮细胞，与表面表皮细胞不同。 CYLD 作为一种去泛素酶，抑制 TRAF2/TRAF6 蛋白（介导细胞表面受体信号转导的关键接头分子）的自身泛素化，从而抑制下游信号通路，包括 NF-κB 和 JNK 信号级联。先前预测的经典 NF-κB 通路在皮肤肿瘤病因学中的作用最近受到了挑战，因为揭示了 TPA 诱导的 cyld-/- 小鼠表皮细胞过度增殖中 NF-κB RelA 功能未改变。此外，我们最近证明 NF-κB 在表皮生长控制中至关重要，其阻断会以 JNK/AP1 功能依赖性方式导致鳞状细胞癌 (SCC)。这些发现使我们推测 CYLD 抑制通过 JNK 级联作用促进肿瘤形成。本研究的首要目标是明确 CYLD 调节表皮细胞生长的机制，并探讨 JNK 信号级联是否在 CYLD 对表皮稳态的影响中发挥核心作用。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，并研究它们对转基因 CYLD 功能以及 JNK 信号传导的生长反应。第二个目标是通过产生小鼠和人类转基因皮肤组织来研究 CYLD 驱动的体内肿瘤形成。我们将研究抑制或增强 NF-κB、JNK 或 Ras-MAPK 信号级联是否会预防或增强 CYLD 诱导的肿瘤。到本提案结束时，我们希望确定 CYLD 调节表皮稳态和皮肤上皮肿瘤的机制。这项工作的前提是，表征皮肤组织中 CYLD 介导的细胞生长和肿瘤形成的分子机制，将为基础上皮生物学提供新的见解，并表征人类皮肤疾病的治疗靶点。