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。然而，正常脑星形胶质细胞如何发育 胶质母细胞瘤仍然是一个谜。鉴定和表征 抑制肿瘤生长的基因可能最终提供合理的 为人类胶质母细胞瘤的早期发现和治疗奠定基础。最近的PI 发现cx43可以逆转人类胶质母细胞瘤的转化表型。 此外，cx43的过度表达显着增强低细胞凋亡 血清状况和对化疗药物的反应。此外， cx43 的表达导致 bc1-2 表达下调。目标在 该资助申请旨在分析肿瘤的分子机制 cx43 与细胞凋亡相关的抑制活性。本期的项目 补助金申请如下： 1).确定功能意义 cx43介导的bc1-2下调和细胞存活途径的研究 细胞凋亡和肿瘤抑制。 2）。确定负责的 CX43 域 CX43 介导的细胞凋亡和肿瘤抑制的激活。细胞系 通过稳定转染建立表达cx43的不同结构域 及其与细胞凋亡激活和抑制相关的功能 肿瘤细胞生长的情况将被确定。 3）。识别和 特异性激活或失活的基因的特征 通过 cDNA 阵列和差异显示检测 cx43 转染细胞。确定 基因表达的功能意义 激活细胞凋亡并抑制肿瘤细胞生长。 4).确定是否 需要核定位或细胞质定位来逆转 使用细胞增殖测定将表型转化为“正常”表型， 软琼脂实验和致瘤实验以及低血清下增强细胞凋亡 健康）状况。这些研究的结果将加深我们对 cx43抑制人胶质母细胞瘤细胞的分子机制 生长。阐明 cx43 参与肿瘤抑制的功能 最终将为细胞凋亡的激活提供分子基础 用于开发抗癌化合物。