APOPTOTIC AND CELL CYCLE GENES IN NEUROBLASTOMA

描述：（改编自研究者摘要） 神经母细胞瘤肿瘤的特征是染色体1带p36的丢失， MYCN扩增特别具有攻击性， 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。 研究从 我们的实验室以及其他实验室已经表明， 当1p36区域缺失时丢失，但迄今为止没有相应的突变 在剩下的等位基因中找到了 然而，一些人的表达 这些基因要么丢失，要么大幅减少，可能是由于 甲基化 此外，我们还发现FasR死亡途径是 细胞周期蛋白D/CDK/INK/pRb通路在大多数人中被灭活， 这些神经母细胞瘤 他们推测，细胞凋亡和细胞凋亡的异常可能是导致细胞凋亡的原因。 细胞周期信号通路是生存所必需的， MYCN扩增的神经母细胞瘤。 我们的理论是， 在MYCN扩增的肿瘤中，FasR通路可能有助于调节高表达的MYCN， 通过允许这些细胞获得对细胞死亡的抵抗力来提高N-myc水平。 此外，1p36的缺失也可能促进了细胞凋亡。 这些细胞中的信号缺陷。 细胞周期蛋白的异常 D/CDK/INK/pRb通路也可能反映重要的细胞反应， 以适应N-myc水平的增加。 为了验证这一假设 并了解细胞凋亡信号的中断和异常 细胞周期的调节协同地促进了 1p36缺失和MYCN扩增的神经母细胞瘤， （1）确定FasR通路在何处被阻断， MYCN扩增和1p36缺失的神经母细胞瘤，以及是否有额外的 死亡途径受到影响;（2）确定为什么p16Ink4a不起作用 通常在这些神经母细胞瘤;（3）确定是否神经母细胞瘤 肿瘤发生需要细胞凋亡和细胞周期的破坏 途径。

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.