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p34cdc2相关的蛋白激酶，细胞周期- 相关的激酶，存在并明显地起着控制各个方面的作用 对细胞周期的调控。这个大家庭的一个成员是PITSLRE 蛋白激酶，p58-PITSLREbeta1。这种蛋白激酶是一种AT PITSLRE家族中至少有10种异构体，所有这些亚型都表达 来自染色体1p36上跨度为-90kb的三个连锁基因。 至少有三种PITSLRE激酶亚型的功能似乎与 细胞凋亡信号转导的效应物。染色体的p36区域 在肿瘤形成的晚期阶段，1经常被缺失 神经母细胞瘤以及其他肿瘤。有几个组织提出了 至少有两个肿瘤抑制基因驻留在该染色体内 区域。神经母细胞瘤细胞中PITSLRE基因座的研究 已有研究表明，这些基因发生了缺失和/或易位 在大多数扩增了N-myc基因的细胞系中。此外，更改了 PITSLRE的一个亚型-的表达 这些细胞系中。基于这些结果，他们提出了 N-myc过度表达带来的增殖优势发生在 凋亡信号通路(S)已被禁用，很可能是由于 部分或完全失活一个或多个PITSLRE蛋白 激酶(S)。突变或消除相关蛋白的表达 凋亡通路可能是肿瘤细胞发展的关键一步。 为了在人类神经母细胞瘤中测试这一假设，他们将进行 这项提案中概述的研究。首先，他们将识别任何 神经母细胞瘤细胞中表达的PITSLRE亚型的遗传损伤 在神经母细胞瘤患者材料中。功能特性 在此筛选中发现的PITSLRE突变体将在体外进行检测 在活体内。其次，野生型PITSLRE激酶的活性将 在神经母细胞瘤细胞中修复含有改变的PITSLRE亚型和 扩增出N-myc基因。神经母细胞瘤细胞与正常对照的能力 PITSLRE激酶水平和正常N-myc水平对实验耐受性的影响 还将测试N-myc的诱导扩增和过度表达。 最后，受体介导的凋亡信号通路中的缺陷 涉及PITSLRE激酶(S)的几个例子中都观察到了 神经母细胞瘤细胞系。他们将对这些路径进行研究，试图 以确定其缺陷的性质。上述研究 将确定单倍体功能不全和/或完全失活 PITSLRE激酶(S)以及N-myc基因的扩增能力 和促进肿瘤生长，是协同的。