REGULATION OF MDRL GENE EXPRESSION IN LIVER AND UTERUS

肝脏和子宫中 MDRL 基因表达的调节

• 批准号: 2096919
• 负责人: MACUS T KUO
• 金额: $ 16.84万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-07 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096919
• 关键词: P glycoprotein; cytogenetics; disease /disorder model; epithelium; gene expression; genetic promoter element; genetic regulation; genetic regulatory element; genetically modified animals; hepatocellular carcinoma; liver; microinjections; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; posttranscriptional RNA processing; steroid hormone; tissue /cell culture; transcription factor; transfection; uterus

Recent studies have revealed that overexpression of multidrug resistance (mdr) gene in some human neoplasms is correlated with poor prognostic responses of these tumors to chemotherapeutic agents. Elucidating the molecular basis of mdr gene expression in normal and in malignant cells may provide important insights into clinical applications of chemotherapy of these tumors. We propose here to investigate the regulation of mouse mdr gene expression in hepatoma-derived cells and in uterine epithelial (UE) cells of pregnant animals. In both cases, mdrl gene is activated. Preliminary results demonstrated that mdrl gene expression can be activated by steroid hormone in hepatoma cells. It is our aim to determine whether the activation mechanism is at the transcriptional or at the posttranscriptional levels and to elucidate the possible hormone responsible DNA elements in the mdrl locus. Furthermore, a 33-bp sequence located in the promoter region of mdrl gene is involved with mdrl expression in hepatoma cells. We propose experiments to further characterize this cis-acting DNA element. Possible trans-activating factor(s) interacting with this DNA element will be purified and genes encoding these factors will be cloned. The activation mechanism of mdrl gene in UE cells during pregnancy will be studied using primary culture derived from UE. This primary culture maintains its apparent in vivo characteristics. The role of steroid hormones in this activation mechanism will be studied; and possible cis-acting DNA sequences in the mdr gene will be determined by transient transfection using microinjection method. These proposed studies may help us to learn the mechanisms of mdr gene regulation in normal and malignant cells.

最近的研究表明，多药耐药的过度表达， (mdr)在某些人类肿瘤中， 这些肿瘤对化疗药物的反应。 阐明 mdr基因在正常和恶性细胞中表达的分子基础可能 为化疗的临床应用提供了重要的见解， 这些肿瘤。 我们在此研究小鼠MDR的调控 肝癌衍生细胞和子宫上皮（UE）中的基因表达 怀孕动物的细胞。 在这两种情况下，mdrl基因被激活。 初步结果表明，mdrl基因表达可以被激活， 类固醇激素在肝癌细胞中的作用。 我们的目标是确定 激活机制是在转录或在 转录后水平并阐明可能的激素 mdrl基因座中负责的DNA元件。 此外，一个33 bp的序列 位于mdrl基因启动子区的p53与mdrl有关 在肝癌细胞中的表达。 我们提出实验，以进一步 描述这种顺式作用的DNA元件。 可能的反式激活 与该DNA元件相互作用的因子将被纯化， 将克隆编码这些因子的基因。 mdrl的激活机制 将使用原代培养研究妊娠期间UE细胞中的基因 源自UE。 这种原代培养物在体内保持其明显的 特色 类固醇激素在这种激活机制中的作用 将进行研究; mdr基因中可能的顺式作用DNA序列将 通过使用显微注射方法的瞬时转染来测定。 这些 这些研究可能有助于我们了解MDR基因调控的机制。 在正常和恶性细胞中。