TRANSCRIPTIONAL CONTROL OF CLASS I P-GLYCOPROTEIN GENES

描述：由于药物的发展，化疗经常失败 抵抗。一种耐药形式，称为多药耐药(MDR) 通常与膜结合药物的表达增加有关 泵，P-糖蛋白(Pgp)，其功能是将MDR药物从 牢房。有三类Pgp基因；MDR最常见的原因是 I类基因的过度表达。在实验室模型中，细胞 表现出I类基因结构性过度表达的可通过以下方式进行选择 持续接触耐多药药物。或者，PGP表达可以是 由于短期接触化疗药物而迅速而短暂地诱发的。 在患者中，I类Pgp的结构性过度表达与 在几种肿瘤类型中存在多药耐药。此外，这方面的初步研究 实验室表明，PGP的快速诱导也可以在人类身上发生 肿瘤。申请者一直在调查哥伦比亚广播公司 参与I类转录的元件/转录因子，并具有 已经确定了几个参与转录的元件 仓鼠第I类启动子的激活。PUP-1是一个二部元素 它与核因子-白介素6和糖皮质激素受体相互作用。MED-1是一种 仅激活Pgp转录所需的CBS元件 在多药耐药细胞中。TIGE是有效激活所必需的元素 第一类PGP启动子。尽管最初的研究利用了 仓鼠I类启动子作为模型系统，许多研究结果也同样适用 对人类系统来说。因此，这个实验室的长远目标是 为了定义和描述两者所涉及的转录成分 人类第I类同源基因的结构性和诱导性表达， MDR1。本申请的目标是1)继续分析 MED-1元件及其同源结合蛋白在培养细胞和 2)进一步评价人PUP-1元件在人类肿瘤中的作用 对各种细胞因子和类固醇激素的反应，长期目标 使用这种方法下调人多药耐药肿瘤中Pgp的表达； 3)探讨染色质在Pgp差异表达中的作用 4)继续Pgp瞬时诱导的分析。 在人类肿瘤和细胞系中的表达，特别强调 多药耐药相关基因CBS元件及转录因子的鉴定 激活。

DESCRIPTION: Chemotherapy often fails due to the development of drug resistance. One form of drug resistance, termed multidrug resistance (MDR) is usually associated with the increased expression of a membrane-bound drug pump, P-glycoprotein (Pgp), which functions to rapidly efflux MDR drugs from the cell. There are three classes of Pgp genes; MDR is most often caused by over-expression of the Class I genes. In laboratory models, cells exhibiting constitutive over-expression of Class I genes can be selected by continuous exposure to MDR drugs. Alternatively, Pgp expression can be rapidly and transiently induced by short-term exposure to chemotherapeutics. In patients, constitutive over-expression of Class I pgp has been associated with MDR in several tumor types. Moreover, preliminary studies in this laboratory indicate that rapid induction of Pgp can also occur in human tumors. The applicants have been investigating the cbs elements/transcription factors involved in Class I transcription, and have already identified several transcriptional elements involved in the activation of the hamster Class I promoter. PUP-1 is a bipartite element which interacts with both NF-IL6 and glucocorticoid receptor. MED-1 is a cbs element which is required only for the activation of Pgp transcription in MDR cells. TIGE is an element which is required for efficient activation of the Class I Pgp promoter. Although the initial studies have utilized the hamster Class I promoter as a model system, many of the findings also apply to the human system. Therefore, the long-range goal of this laboratory is to define and characterize the transcriptional components involved in both the constitutive and inducible expression of the human Class I homologue, MDR1. The goals of the present application are 1) to continue the analysis of the MED-1 element and its cognate binding proteins in cultured cells and human tumors; 2) to further evaluate the role of the human PUP-1 element in response to various cytokines and steroid hormones, with the long-range goal of using this approach to down-regulate Pgp expression in human MDR tumors; 3) to evaluate the role of chromatin in the differential expression of Pgp genes; and 4) to continue the analysis of transient induction of Pgp expression in human tumors and cell lines, with particular emphasis on the identification of cbs elements and transcriptional factors involved in MDR1 activation.