DNA METHYLATION AND SOD2/MNSOD GENE EXPRESSION

DNA 甲基化和 SOD2/MNSOD 基因表达

基本信息

批准号：
6513058
负责人：
FREDERICK E DOMANN
金额：
$ 11.11万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-06 至 2003-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6513058
关键词：
CpG islands DNA methylation enzyme activity enzyme induction /repression genetic promoter element human genetic material tag molecular cloning reporter genes superoxide dismutase tissue /cell culture transcription factor tumor suppressor genes tumor suppressor proteins

项目摘要

DESCRIPTION: The objectives of this project are to investigate the role of DNA methylation on the regulation of the SOD2 gene, a putative tumor suppressor gene, which encodes the antioxidant enzyme manganese superoxide dismutase (MnSOD). While it is generally accepted that in malignant cells SOD2 is expressed at lower levels than in normal cells, the mechanisms underlying this differential expression are not known. However, numerous studies have pointed to the participation of tumor suppression genes whose expression is modulated by genomic methylation patterns, and which are believed to contribute to differentiation and carcinogenesis. The central hypothesis of this project is that cytosine methylation in the CpG islands surrounding the SOD2 gene transcription start site can adversely influence the expression of SOD2. Specific aim #1 is to map the human SOD2 gene for cis-acting regulatory elements that participate in governing its expression. In specific aim #2, the hypothesis will be tested that hypermethylation of CpG island in the human SOD gene promoter can block the expression of a reporter gene in a non-malignant cell line known to express SOD2 (the WI-38 human lung fibroblast cell line). I specific aim #3 the hypothesis will be tested that a decreased SOD2 expression in cancer cells relative to their normal cell counterparts is due to differential methylation of the SOD2 promoter. Specific aim #4 is to determine the effects of methylation and transcription factor availability on the transcriptional activation of the SOD2 promoter in malignant and non-malignant cells. A better understanding of the mechanisms of regulation of the expressio of SOD2 during carcinogenesis and differentiation may lead to new strategies for the treatment of diseases in which aberrant SOD2 expression plays a key role.

描述：该项目的目标是调查 DNA甲基化对SOD2基因的调节，一种假定的肿瘤抑制基因，该基因编码抗氧化剂锰超氧化物歧化酶（MNSOD）。虽然普遍认为在恶性细胞中 SOD2的水平低于正常细胞的水平，这些机制尚不清楚这种差异表达的基础。但是，很多研究表明，肿瘤抑制基因的参与表达是由基因组甲基化模式调节的，它们是被认为有助于分化和致癌作用。中央该项目的假设是CPG岛中的胞嘧啶甲基化围绕SOD2基因转录起始位点可能会对 SOD2的表达。特定目的＃1是映射人类SOD2基因的参与其表达的顺式作用调节元素。在特定的目标＃2中，将检验假设的过度甲基化人草皮基因启动子中的CpG岛可以阻止已知表达SOD2的非恶性细胞系中的报告基因（WI-38 人肺成纤维细胞系）。我具体的目标＃3假设将是测试表明，癌细胞中SOD2的表达降低了正常细胞对应是由于SOD2的差异甲基化引起的发起人。特定目的＃4是确定甲基化和转录因子的转录因子在转录激活中的可用性恶性细胞和非恶性细胞中的SOD2启动子。更好的理解 SOD2表达的调节机制癌变和分化可能会导致新的策略异常SOD2表达的疾病治疗起着关键作用。