JUN PROTEINS IN EPIDERMAL HOMEOSTASIS AND NEOPLASIA

Jun 蛋白在表皮稳态和肿瘤形成中的作用

• 批准号: 8131846
• 负责人: Jennifer Yunyan Zhang
• 金额: $ 33.91万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131846
• 关键词: Accounting; Advanced Malignant Neoplasm; Affect; Arthritis; Atopic Dermatitis; Basal cell carcinoma; Binding; Biology; Cell Aging; Cell Cycle; Cell Death; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Chemicals; Chronic; Complex; DNA Binding Domain; Data; Dermal; Diagnostic Neoplasm Staging; Differentiation Antigens; Differentiation and Growth; Disease; Dominant-Negative Mutation; Dose; EGF gene; Epidermis; Epithelial; Equilibrium; Family; Fibroblasts; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Growth; Homeostasis; Human; Hyperplasia; Individual; Inflammatory; JUN gene; JUNB gene; Lymphocyte; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutation; N-terminal; Nature; Neoplasms; Pathogenesis; Patients; Personal Satisfaction; Phenotype; Phosphotransferases; Population; Process; Proteins; Proto-Oncogene Proteins c-jun; Psoriasis; Regulation; Reporting; Role; Signal Transduction; Signaling Molecule; Skin; Skin Abnormalities; Specificity; Squamous cell carcinoma; Stratification; Structure; Tertiary Protein Structure; Testing; Tissues; Transactivation; Transcription Factor AP-1; Tumor Suppressor Proteins; base; cell growth; clinical phenotype; clinically relevant; design; filaggrin; genome-wide; inhibitor/antagonist; insight; keratinocyte; loss of function; member; neoplastic; overexpression; paracrine; prevent; promoter; public health relevance; response; self-renewal; skin disorder; stress-activated protein kinase 1; synergism; therapeutic target; transcription factor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Epidermis undergoes continuous self-renewal through a tight balance of cell proliferation, differentiation and cell death. This balance is regulated by both epidermal cell-intrinsic processes and paracrine effects from dermal cells, including fibroblasts and lymphocytes. Among a complex array of signaling molecules and transcription factors, the IKK/NF-: B and JNK/AP-1 signaling cascades have been implicated as dominant regulators in mediating epidermal cell-intrinsic processes. NF-: B controls epidermal growth, while AP-1 induction via JNK is responsible for the epidermal hyperplasia and neoplasia associated with NF-: B blockade. However, there are functional diversities and even antagonisms among AP-1 subunits. Specifically, although both JunB and c-Jun are involved in mediating epidermal differentiation markers, JunB inhibits epidermal cell growth and induces cell senescence; whereas c-Jun promotes epidermal growth and neoplasia. Moreover, epidermal-specific deletion of JunB alone or along with c-Jun, but not c-Jun alone, in mice leads to an inflammatory skin phenotype with resemblance to human arthritic and psoriatic diseases. These findings underscore important roles for JunB and c-Jun in epidermal well-being and pathogenesis, and suggest that they are functionally antagonistic and redundant in mediating epidermal cell growth and differentiation, respectively. The first goal of this proposal is to determine the molecular mechanisms of Jun proteins in mediating epidermal cell-intrinsic processes. To do this, we will perform systemic structure-functional studies to define the functional specificity of JunB and c-Jun sub-domains in epidermal growth and differentiation. We will also determine the nature of the antagonism or synergism between JunB and c- Jun, and identify their downstream target genes by genome-wide gene expression analysis. The second goal is to determine how JunB and c-Jun contribute to epidermal tumorigenesis. To do this, we will use the recently established human squamous cell carcinoma models to examine gain- or loss-of-function effects of JunB and c-Jun, as well as their downstream target, p16, on epidermal tumor growth, maintenance and regression. This effort is based on the premise that characterizing the molecular mechanisms governing the functional specificity of JunB and c-Jun will provide new insights into both basic epithelial biology and better defined therapeutic targets. PUBLIC HEALTH RELEVANCE: Abnormalities of epidermal growth or differentiation account for many diseases affecting a large proportion of the U.S. population. Among these disorders are atopic dermatitis, psoriasis, squamous cell carcinoma, basal cell carcinoma and chronic wounds. The efforts of this proposal are designed to characterize the genetic regulatory mechanisms governing epidermal homeostasis and neoplastic pathogenesis, and therefore provide meaningful insights to better defined therapeutic targets for skin disorders as well as other types of diseases.

描述（由申请人提供）：表皮通过细胞增殖，分化和细胞死亡的紧密平衡而经历连续的自我更新。这种平衡受皮肤细胞的表皮细胞中性过程和旁分泌作用的调节，包括成纤维细胞和淋巴细胞。在复杂的信号分子和转录因子中，IKK/NF-：B和JNK/AP-1信号传导级联反应被视为介导表皮细胞内膜过程中的主要调节剂。 NF-：B控制表皮生长，而通过JNK诱导的AP-1诱导负责与NF-：B阻滞相关的表皮增生和肿瘤。但是，AP-1亚基之间存在功能多样性甚至对抗。具体而言，尽管JunB和C-Jun都参与介导表皮分化标记，但JUNB抑制表皮细胞的生长并诱导细胞衰老。而c-Jun促进表皮生长和肿瘤。此外，在小鼠中，单独或与C-Jun一起单独或与C-Jun一起进行表皮特异性缺失，导致炎症性皮肤表型，与人类关节炎和牛皮癣疾病相似。这些发现强调了JUNB和C-JUN在表皮健康和发病机理中的重要作用，并表明它们在功能上具有拮抗作用，并且分别在介导表皮细胞的生长和分化中是多余的。 该提案的第一个目标是确定介导表皮细胞中性过程中JUN蛋白的分子机制。为此，我们将进行系统性结构功能研究，以定义JunB和C-Jun子域在表皮生长和分化中的功能特异性。我们还将确定Junb和C Jun之间对抗或协同作用的性质，并通过全基因组基因表达分析来识别其下游靶基因。第二个目标是确定JUNB和C-JUN如何促进表皮肿瘤发生。为此，我们将使用最近建立的人类鳞状细胞癌模型来检查JUNB和C-JUN的功能丧失效应，以及其下游靶标对表皮肿瘤生长，维持和回归的下游靶标。这项工作是基于以下前提：表征统治JunB和C-Jun功能特异性的分子机制将为基本上皮生物学和更好定义的治疗靶标提供新的见解。 公共卫生相关性：表皮增长或分化的异常是影响大部分美国人群的许多疾病。这些疾病包括特应性皮炎，牛皮癣，鳞状细胞癌，基底细胞癌和慢性伤口。该提案的努力旨在表征有关表皮稳态和肿瘤发病机理的遗传调节机制，因此为皮肤疾病以及其他类型的疾病提供了有意义的见解。