APOPTOTIC AND CELL CYCLE GENES IN NEUROBLASTOMA

神经母细胞瘤中的凋亡和细胞周期基因

• 批准号: 2895315
• 负责人: VINCENT J. KIDD
• 金额: $ 31.83万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-15 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895315
• 关键词: apoptosis; biological signal transduction; carcinogenesis; cell cycle; cell growth regulation; cell line; cyclin dependent kinase; cyclins; cysteine endopeptidases; gene deletion mutation; gene expression; genetic library; genetic regulation; methylation; molecular cloning; natural gene amplification; neuroblastoma; nucleic acid sequence; tissue /cell culture; transfection; western blottings; yeast two hybrid system

DESCRIPTION: (adapted from the investigator's abstract) A subset of neuroblastoma tumors characterized by the loss of chromosome 1 band p36 and MYCN amplification are particularly aggressive and have a particularly bad prognosis. In addition, many of these tumors no longer respond to chemotherapeutic drugs, making their treatment very difficult. Studies from our lab, as well as others, have shown that a number of apoptotic genes are lost when the 1p36 region is deleted, but so far no corresponding mutations have been found in the remaining allele. However, the expression of several of these genes is either lost of substantially diminished, possibly by methylation. Furthermore, we have found that the FasR death pathway is inactivated and the cyclin D/CDK/INK/pRb pathway altered in the majority of these neuroblastomas. They hypothesize that abnormalities in apoptotic and cell cycle signaling pathways are necessary for the survival of neuroblastomas with amplified MYCN. We theorize that the inactivation of the FasR pathway in tumors with amplified MYCN may help to accommodate high levels of N-myc by allowing these cells to acquire resistance to cell death. In addition, the deletion of 1p36 may also contribute to the apoptotic signaling defect(s) in these cells. The abnormalities in the cyclin D/CDK/INK/pRb pathway may also reflect important cellular responses that are necessary to accommodate increased levels of N-myc. To test this hypothesis and to understand whether the disruption of apoptotic signaling and abnormal regulation of the cell cycle synergistically contribute to the progression of neuroblastoma with 1p36 loss and MYCN amplification they propose to do the following: (1) determine where the FasR pathway is blocked in neuroblastomas with MYCN amplification and 1p36 loss, and whether additional death pathways are affected; (2) determine why p16Ink4a does not function normally in these neuroblastomas; (3) determine whether neuroblastoma tumorigenesis requires the disruption of both apoptotic and cell cycle pathways.

描述：（根据调查员的摘要进行了改编） 神经母细胞瘤肿瘤的特征是染色体1带P36和 MYCN放大特别侵略性，并且特别糟糕 预后。 此外，其中许多肿瘤不再反应 化学治疗药物，使其治疗非常困难。 研究 我们的实验室以及其他实验室都表明，许多凋亡基因是 当删除1P36区域时丢失，但到目前为止尚无相应的突变 在其余等位基因中发现。 但是，几个的表达 这些基因的损失大大减少，可能是由于 甲基化。 此外，我们发现FASR死亡道路是 灭活和细胞周期蛋白D/CDK/墨水/PRB途径在大多数情况下发生了变化 这些神经母细胞瘤。 他们假设凋亡和 细胞周期信号传导途径对于生存是必要的 神经母细胞瘤和放大的mycn。 我们从理论上说 放大MYCN的肿瘤中的FASR途径可能有助于容纳高 通过允许这些细胞获得对细胞死亡的抗性，N-MYC的水平。 此外，136的删除也可能导致凋亡 这些细胞中的信号缺陷。 细胞周期蛋白异常 D/CDK/墨水/PRB途径也可能反映出重要的细胞反应 需要增加N-MYC水平的必要条件。 检验这一假设 并了解凋亡信号传导和异常的破坏是 细胞周期的调节协同有助于进展 他们提议做的神经母细胞瘤，具有1P36损失和MYCN扩增 以下内容：（1）确定FASR途径在哪里阻塞 神经母细胞瘤带有MYCN扩增和1P36损失，以及是否附加 死亡道路受到影响； （2）确定为什么p16ink4a不起作用 通常在这些神经母细胞瘤中； （3）确定神经母细胞瘤是否 肿瘤发生需要破坏凋亡和细胞周期 途径。