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: 8272464
• 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/8272464
• 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进行持续的自我更新。这种平衡受到表皮细胞固有过程和真皮细胞（包括成纤维细胞和淋巴细胞）的旁分泌作用的调节。在一系列复杂的信号分子和转录因子中，IKK/NF-:B 和 JNK/AP-1 信号级联被认为是介导表皮细胞内在过程的主要调节因子。 NF-:B 控制表皮生长，而通过 JNK 诱导 AP-1 则负责与 NF-:B 阻断相关的表皮增生和肿瘤形成。然而，AP-1亚基之间存在功能多样性甚至拮抗作用。具体来说，虽然JunB和c-Jun都参与介导表皮分化标志物，但JunB抑制表皮细胞生长并诱导细胞衰老；而 c-Jun 促进表皮生长和肿瘤形成。此外，在小鼠中，单独或与c-Jun一起（但不是单独的c-Jun）表皮特异性缺失JunB会导致类似于人类关节炎和银屑病疾病的炎症性皮肤表型。这些发现强调了 JunB 和 c-Jun 在表皮健康和发病机制中的重要作用，并表明它们分别在介导表皮细胞生长和分化方面具有功能拮抗性和冗余性。 该提案的第一个目标是确定 Jun 蛋白介导表皮细胞内在过程的分子机制。为此，我们将进行系统结构功能研究，以确定 JunB 和 c-Jun 子结构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之间拮抗或协同的性质，并通过全基因组基因表达分析来鉴定其下游靶基因。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 及其下游靶标 p16 对表皮肿瘤生长、维持和消退的功能获得或丧失的影响。这项工作的前提是，表征控制 JunB 和 c-Jun 功能特异性的分子机制将为基础上皮生物学和更好定义的治疗靶点提供新的见解。 公共卫生相关性：表皮生长或分化异常是影响美国大部分人口的许多疾病的原因。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。该提案的工作旨在描述控制表皮稳态和肿瘤发病机制的遗传调控机制，从而为更好地确定皮肤病以及其他类型疾病的治疗靶点提供有意义的见解。