STEROID CONTROL OF EPITHELIAL CELL-CELL INTERACTIONS

描述：（改编自研究者摘要）：类固醇激素 细胞间相互作用的控制是一种潜在的重要调节机制， 促进质膜协调和复杂变化的机制 组成、功能和细胞内信号传导。先前已经 记录了糖皮质激素，一类类固醇激素， 在致瘤性和非致瘤性细胞单层培养中， 非致瘤性乳腺上皮细胞，暗示这种催乳类固醇是 一个关键的体内调节细胞接触在分化过程中的细胞， 乳腺糖皮质激素刺激紧密连接的募集 蛋白质、粘附连接蛋白和两种信号分子 细胞间的接触这一交界性重组过程之后， 不同的Ras依赖性步骤，导致形成高度密封的紧密 交叉点糖皮质激素的几个关键调节成分 类固醇控制紧密连接所需的信号级联 在乳腺上皮细胞中的动力学，已经被发现。中的早期事件 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， 交互.糖皮质激素调节的一种新的强直相关闭塞蛋白 利用酵母双杂交技术克隆了一个尾部相互作用蛋白（GAO 屏幕我们认为GAO将类固醇诱导的级联反应与紧密的 连接结构蛋白该提案的一个目的是描述 GAO的结构/功能特性，并确定其在控制 通过野生型、突变型和反义GAO表达的紧密连接动力学 序列在乳腺上皮细胞肿瘤细胞中的表达， 透化细胞的操作。这项建议的另一个目的是 鉴定并功能性表征Id-1的细胞靶点， 乳腺上皮细胞配对差异基因芯片筛选 选择性改变Id-1表达的细胞。细胞-细胞相互作用 在控制正常细胞的生长和分化方面起着关键作用， 组织，而恶性表型与这种破坏有关。 过程来自拟议研究的信息最终可能被证明是 临床上可用于治疗策略的潜在开发， 控制生理性疾病和肿瘤， 质膜功能、粘附和细胞内通讯。

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.