SUPPRESSION OF HUMAN GLIOBLASTOMA CELL GROWTH BY CX43

CX43 对人胶质母细胞瘤细胞生长的抑制

• 批准号: 6378194
• 负责人: RUO-PAN HUANG
• 金额: $ 22.98万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378194
• 关键词: BCL2 gene /protein; apoptosis; astrocytoma; cell growth regulation; cell line; cell proliferation; complementary DNA; gap junctions; gene induction /repression; laboratory mouse; membrane channels; molecular cloning; neoplastic growth; northern blottings; nucleic acid sequence; oligonucleotides; polymerase chain reaction; tumor suppressor proteins

Brain tumors are one of the leading causes of death among young children and adults. Glioblastomas are the most common primary brain tumors and are among the deadliest of tumors. However, how normal brain astrocytes develop into glioblastoma still remains a mystery. Identification and characterization of genes which can suppress tumor growth may eventually provide a rational basis for early detection and treatment of human glioblastoma. The PI recently found that cx43 can reverse the transformed phenotype of human glioblastomas. Furthermore, over-expression of cx43 significantly enhances apoptosis in low serum conditions and in response to chemotherapeutic agents. Furthermore, expression of cx43 leads to down-regulation of bc1-2 expression. The goals in this grant application are to analyze the molecular mechanisms of tumor suppression activity in relation to apoptosis by cx43. The projects in this grant application will be as follows: 1). Determine the functional significance of down-regulation of bc1-2 and cells survival pathway in cx43 mediated apoptosis and tumor suppression. 2). Determine the cx43 domains responsible for the activation of cx43-mediated apoptosis and tumor suppression. The cell lines expressing different domains of cx43 will be established by stable transfection and their function in relation to the activation of apoptosis and suppression of tumor cell growth will be determined. 3). Identification and characterization of the genes specifically activated or inactivated in cx43-transfected cells by cDNA array and differential display. Determine the functional significance of gene expressions identified with respect to the activation of apoptosis and suppression of tumor cell growth. 4). Determine if nuclear localization or cytoplasm localization is required to reverse the transformed phenotype to a "normal" phenotype using cell proliferation assay, soft agar assay and tumorigenicity assay and enhance apoptosis under low serum condition. The results from these studies will enhance our understanding of the molecular mechanism of cx43 in the suppression of human glioblastoma cell growth. The elucidation of cx43 function involved in the tumor suppression with respect to activation of apoptosis eventually will provide a molecular basis for the development of anti-cancer compounds.

脑肿瘤是年轻人死亡的主要原因之一 儿童和成人。胶质母细胞瘤是最常见的原发性脑肿瘤， 是最致命的肿瘤之一。但是，正常的大脑星形胶质细胞如何发展 进入胶质母细胞瘤仍然是一个谜。识别和表征 可以抑制肿瘤生长的基因最终可能提供合理的 早期检测和治疗人胶质母细胞瘤的基础。 PI最近 发现CX43可以扭转人胶质母细胞瘤的转化表型。 此外，CX43的过表达显着增强了低凋亡 血清条件和对化学治疗剂的反应。此外， CX43的表达导致BC1-2表达的下调。目标 该赠款应用是分析肿瘤的分子机制 CX43与凋亡有关的抑制活性。其中的项目 授予申请如下：1）。确定功能意义 BC1-2的下调和CX43中介导的细胞存活途径 凋亡和肿瘤抑制。 2）。确定负责的CX43域 CX43介导的凋亡和肿瘤抑制的激活。细胞系 表达CX43的不同域将通过稳定转染建立 以及它们与凋亡和抑制激活有关的功能 将确定肿瘤细胞生长的生长。 3）。识别和 特异性激活或灭活的基因的表征 CX43转染的细胞通过cDNA阵列和差分显示。确定 基因表达的功能显着性相对于 凋亡的激活和肿瘤细胞生长的抑制。 4）。确定是否 需要核定位或细胞质定位才能扭转 使用细胞增殖测定法转化为“正常”表型的表型， 软琼脂测定法和肿瘤性测定并在低血清下增强凋亡 健康）状况。这些研究的结果将增强我们对 CX43的分子机制在抑制人胶质母细胞瘤细胞中 生长。与肿瘤抑制有关的CX43功能的阐明 尊重凋亡的激活最终将提供分子基础 为了开发抗癌化合物。