APOPTOTIC AND CELL CYCLE GENES IN NEUROBLASTOMA

描述：(改编自调查人员的摘要) 神经母细胞瘤的特征是染色体1带p36和 MYCN扩增尤其具有攻击性，并且具有特别糟糕的 预后。此外，这些肿瘤中的许多不再对 化疗药物，使他们的治疗非常困难。研究来自 我们的实验室和其他实验室一样，已经证明了一些凋亡基因是 当1p36区域缺失时丢失，但到目前为止还没有相应的突变 已在剩余的等位基因中发现。然而，表达了几个 这些基因要么丢失，要么大幅减少，可能是通过 甲基化。此外，我们还发现FasR的死亡途径是 大多数细胞周期蛋白D/CDK/INK/PRB通路失活和改变 这些神经母细胞瘤。他们假设，细胞凋亡和细胞周期的异常 细胞周期信号通路是细胞存活所必需的 扩增MYCN的神经母细胞瘤。我们的理论是，失活 扩增了MYCN的肿瘤中的FasR通路可能有助于调节 通过使这些细胞获得对细胞死亡的抵抗力来提高N-myc的水平。 此外，1p36的缺失也可能导致细胞凋亡 这些细胞中存在信号缺陷(S)。自行车运动中的异常现象 D/CDK/INK/PRB通路也可能反映了重要的细胞反应 这是适应N-myc水平增加所必需的。为了检验这一假说 并了解细胞凋亡信号的中断和异常 细胞周期的调节协同作用促进了这一进程 神经母细胞瘤的1p36缺失和MYCN扩增 以下内容：(1)确定FasR通路被阻断的位置 具有MYCN扩增和1p36缺失的神经母细胞瘤 死亡途径受到影响；(2)确定p16INK4a不起作用的原因 通常在这些神经母细胞瘤中；(3)确定神经母细胞瘤 肿瘤的发生需要破坏细胞的凋亡和细胞周期 小路。

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.