TRANSCRIPTIONAL CONTROL OF CLASS I P-GLYCOPROTEIN GENES

描述：由于药物的发展，化疗经常失败 阻力 一种形式的耐药性，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），其功能是快速外排MDR药物， 牢房 有三类Pgp基因; MDR最常由以下引起： I类基因的过度表达。 在实验室模型中， 表现出I类基因组成型过表达的基因可通过以下方法选择 持续暴露于MDR药物。 或者，Pgp表达可以是 通过短期暴露于化疗药物快速和短暂诱导。 在患者中，I类pgp的组成性过度表达与 在几种肿瘤类型中具有MDR。 此外，在这方面的初步研究 实验室表明Pgp快速诱导也可发生在人中 肿瘤的 申请人一直在调查cbs 参与I类转录的元件/转录因子，并且具有 已经确定了几个转录元件参与了 激活仓鼠I类启动子。 PUP-1是一个二分元素 其与NF-IL 6和糖皮质激素受体两者相互作用。 MED-1是一种 cbs元件，其仅为激活Pgp转录所需 在MDR细胞中。 TIGE是有效激活所需的元素 I类Pgp启动子。 虽然最初的研究利用了 仓鼠I类启动子作为模型系统，许多研究结果也适用 to the human人的system系统. 因此，该实验室的长期目标是 来定义和表征参与这两个过程的转录成分， 人I类同源物的组成型和诱导型表达， 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中的表达， 2）进一步评估人PUP-1元件在人肿瘤中的作用， 对各种细胞因子和类固醇激素的反应，长期目标是 使用这种方法下调Pgp在人MDR肿瘤中的表达; 3)探讨染色质在Pgp差异表达中的作用 基因;以及4）继续分析Pgp的瞬时诱导 在人肿瘤和细胞系中的表达，特别强调 MDR 1相关cbs元件和转录因子的鉴定 activation.

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.