STEROID CONTROL OF EPITHELIAL CELL-CELL INTERACTIONS

描述：(改编自《调查者摘要》)：类固醇激素 细胞间相互作用的控制是一项潜在的重要调控 促进质膜协调和复杂变化的机制 组成、功能和细胞内信号转导。以前是这样的 文献证明，糖皮质激素是一种类固醇激素，能引起紧张 体外培养的人成瘤细胞单层的连接形成和细胞极性 非致瘤乳腺上皮细胞，暗示这种乳源性类固醇是 细胞分化过程中细胞-细胞接触的关键调节因子 乳腺。糖皮质激素刺激紧密连接的募集 蛋白质、粘着连接蛋白和两个信号分子连接到这些位点 细胞间的接触。这一交界性重组过程之后是一个 独特的RAS依赖步骤，导致形成高度密封的致密层 交汇点。糖皮质激素的几个关键调节成分 激素控制紧密连接所需的信号级联反应 乳腺上皮细胞的动力学，已经被发现。在中国的早期活动 该级联反应是糖皮质激素刺激的ID-1的表达 转录调节因子。据推测，ID-1改变了 一组特定的靶基因，最终调节乳腺细胞-细胞 互动。一种新的糖皮质激素调节的锚蛋白相关闭塞 利用酵母双杂交技术克隆了尾部相互作用蛋白(命名为GAO) 屏幕上。有人认为，GAO将类固醇诱导的级联反应与紧张性 连接结构蛋白。这项提案的一个目标是描述 GAO的结构/功能特性及其在调控中的作用 野生型、突变型和反义GAO表达的紧密连接动力学 乳腺上皮细胞肿瘤细胞中的序列及其体外检测 通透性细胞的操作。这项提议的另一个目的是 通过一种方法鉴定ID-1的细胞靶标并对其进行功能鉴定 配对乳腺上皮细胞差异DNA微阵列筛选 ID-1表达选择性改变的细胞。细胞间相互作用 在控制正常细胞生长和分化中起关键作用 组织，然而，恶性表型与这一区域的破坏有关 进程。来自拟议研究的信息最终可能被证明是 在临床上有用的潜在的治疗策略的发展 控制生理紊乱和肿瘤的明显变化 质膜功能、黏附和细胞内通讯。

DESCRIPTION: (Adapted from the Investigator's Abstract): The steroid hormone control of cell-cell interactions is a potentially important regulatory mechanism to facilitate coordinated and intricate changes in plasma membrane composition, function and intracellular signaling. It has been previously documented that glucocorticoids, one class of steroid hormones, induce tight junction formation and cell polarity in cultured monolayers of tumorigenic and nontumorigenic mammary epithelial cells, implicating this lactogenic steroid as a key in vivo regulator of cell-cell contact during differentiation of the mammary gland. Glucocorticoids stimulate the recruitment of the tight junction proteins, adherent junction proteins and two signaling molecules to the sites of cell-cell contact. This junctional reorganization process is followed by a distinct Ras-dependent step that results in formation of highly sealed tight junctions. Several critical regulatory components of the glucocorticoid signaling cascade that are required for the steroid control of tight junction dynamics in mammary epithelial cells, have been uncovered. An early event in the cascade is the glucocorticoid stimulated expression of the Id-1 transcriptional regulator. It is postulated that Id-1 alters the expression of a specific set of target genes that ultimately regulate mammary cell-cell interactions. A novel glucocorticoid-regulated ankyrin-related occludin tail-interacting protein (named GAO) has been cloned using a yeast two-hybrid screen. It is proposed that GAO links the steroid induced cascade to the tight junction structural proteins. One aim of this proposal is to characterize the structure/function properties of GAO and determine its role in the control of tight junction dynamics by expression of wild type, mutated and antisense GAO sequences in mammary epithelial cell tumor cells and by the in vitro manipulations of permeabilized cells. The other aim of this proposal is to identify and functionally characterize the cellular targets of Id-1 by a differential DNA microarray screen between matched pairs of mammary epithelial cells with selective alterations in Id-1 expression. Cell-cell interactions play a critical role in controlling the growth and differentiation of normal tissue, whereas, the malignant phenotype is associated with disruptions in this process. Information from the proposed studies may eventually prove to be clinically useful in the potential development of therapeutic strategies to control physiologic disorders and neoplasias with apparent alterations in plasma membrane function, adhesion and intracellular communication.