JUN PROTEINS IN EPIDERMAL HOMEOSTASIS AND NEOPLASIA

描述(申请人提供)：表皮通过细胞增殖、分化和细胞死亡之间的紧密平衡进行持续的自我更新。这种平衡既受表皮细胞内在过程的调节，也受真皮细胞(包括成纤维细胞和淋巴细胞)的旁分泌效应调节。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。核因子-：B控制表皮生长，而通过JNK诱导的AP-1负责与核因子-：B阻断相关的表皮增生和肿瘤。然而，AP-1亚基之间存在功能差异甚至拮抗作用。具体地说，虽然JunB和c-jun都参与了表皮分化标志物的调节，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发生。此外，在小鼠中，单独或与c-jun一起缺失JunB，而不是单独缺失c-jun，会导致类似于人类关节炎和牛皮癣疾病的炎性皮肤表型。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，并表明它们在调节表皮细胞生长和分化方面分别具有功能拮抗性和冗余性。这项建议的第一个目标是确定Jun蛋白在介导表皮细胞内在过程中的分子机制。为此，我们将进行系统的结构-功能研究，以确定JunB和c-jun亚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之间的拮抗或协同作用的性质，并通过全基因组基因表达分析来确定它们的下游靶基因。第二个目标是确定JunB和c-jun在表皮肿瘤发生中的作用。为此，我们将使用最近建立的人鳞状细胞癌模型来检测JunB和c-jun及其下游靶点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地确定治疗靶点提供新的见解。

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.