PITSLRE KINASE GENE ALTERATIONS IN NEUROBLASTOMA

神经母细胞瘤中 PITSLRE 激酶基因的改变

• 批准号: 2443159
• 负责人: VINCENT J. KIDD
• 金额: $ 22.53万
• 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 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443159
• 关键词: apoptosis; biological signal transduction; carcinogenesis; cell cycle proteins; cell growth regulation; chromosome deletion; chromosome translocation; enzyme activity; gene expression; human genetic material tag; natural gene amplification; neuroblastoma; protein isoforms; tissue /cell culture; tumor suppressor genes

DESCRIPTION: A group of protein kinases related to p34cdc2, cell cycle- related kinases, exist and apparently function to control various aspects of cell cycle regulation. One member of this family is the PITSLRE protein kinase, p58-PITSLREbeta1. This protein kinase is one of at least ten isoforms in the PITSLRE family, all of which are expressed from three tandemly linked genes spanning -90 kb on chromosome 1p36. At least three of the PITSLRE kinase isoforms appear to function as effectors of apoptotic signal transduction. The p36 region of chromosome 1 is frequently deleted during the late stages of tumorigenesis in neuroblastoma, as well as other tumors. Several groups have proposed that at least two tumor suppressor genes reside within this chromosome region. The studies of the PITSLRE gene locus in neuroblastoma cell lines have shown that deletion and/or translocation of these genes occur in most cell lines with amplified N-myc genes. Furthermore, altered expression of one PITSLRE isoform, gamma1, was also observed in several of these cell lines. Based on these results, they have proposed that the proliferative advantage offered by N-myc overexpression occurs after apoptotic signaling pathway(s) have been disabled, most likely due to the partial of complete inactivation of one or more of the PITSLRE protein kinase(s). Mutating or extinguishing the expression of proteins involved in apoptotic pathways may be a critical step in tumor cell development. To test this hypothesis in human neuroblastoma they will perform the studies outlined in this proposal. First, they will identify any genetic lesions in the PITSLRE isoforms expressed in neuroblastoma cell lines and in neuroblastoma patient material. The functional properties of PITSLRE mutants identified in this screen will be assayed in vitro and in vivo. Secondly, wild-type PITSLRE kinase activity will be restored in neuroblastoma cells containing altered PITSLRE isoforms and amplified N-myc genes. The ability of neuroblastoma cells with normal PITSLRE kinase levels and normal N-myc levels to tolerate experimentally induced amplification and overexpression of N-myc will also be tested. Finally, defects in receptor-mediated apoptotic signaling pathways involving PITSLRE kinase(s) have been observed in several of these neuroblastoma cell lines. They will examine these pathways in an attempt to determine the nature of their defect. The studies described above will establish whether haploinsufficiency and/or total inactivation of the PITSLRE kinase(s), as well as the ability of N-myc genes to amplify and enhance tumor growth, are synergistic.

描述：一组与p34 cdc 2、细胞周期相关的蛋白激酶。 相关激酶，存在并显然起着控制各个方面的作用 细胞周期调控的关键。 这个家族的一个成员是PITSLRE 蛋白激酶，p58-PITSLRE β 1。 这种蛋白激酶是一种 PITSLRE家族中的至少十种同种型，所有这些同种型均表达于 来自染色体1 p36上跨越~ 90 kb的三个串联连锁基因。 至少有三种PITSLRE激酶亚型似乎起作用， 凋亡信号转导的效应子。 染色体p36区 1在肿瘤发生的晚期经常缺失， 神经母细胞瘤以及其他肿瘤。 有几个团体建议 至少有两个肿瘤抑制基因存在于这条染色体上 地区 神经母细胞瘤细胞PITSLRE基因位点的研究 株系已经显示这些基因的缺失和/或易位发生 在大多数具有扩增N-myc基因的细胞系中。 此外，改变 在几个组织中也观察到一种PITSLRE亚型γ 1的表达， 这些细胞系。 根据这些结果，他们提出， N-myc过表达提供的增殖优势发生在 细胞凋亡信号通路已被禁用，最有可能是由于 一种或多种PITSLRE蛋白的部分或完全失活 激酶。 突变或消除相关蛋白质的表达 可能是肿瘤细胞发展的关键步骤。 为了在人类神经母细胞瘤中验证这一假设，他们将进行 研究报告中提到了这一建议。 首先，他们将确定任何 神经母细胞瘤细胞中表达的PITSLRE亚型的遗传性病变 线和神经母细胞瘤患者材料中。 功能特性 将在体外测定在该筛选中鉴定的PITSLRE突变体的 和体内。 第二，野生型PITSLRE激酶活性将被抑制。 在含有改变的PITSLRE亚型的神经母细胞瘤细胞中恢复， 扩增N-myc基因。 神经母细胞瘤细胞与正常人的能力 PITSLRE激酶水平和正常N-myc水平，以耐受实验 还将测试N-myc的诱导扩增和过表达。 最后，受体介导的凋亡信号通路的缺陷 已经在其中几种中观察到涉及PITSLRE激酶的 神经母细胞瘤细胞系。 他们将研究这些途径， 来确定他们的缺陷 上述研究 将确定是否单倍不足和/或完全失活 PITSLRE激酶以及N-myc基因扩增的能力 和促进肿瘤生长是协同的。