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，细胞周期有关的蛋白激酶 相关激酶，存在并显然起作用以控制各个方面 细胞周期调节。 这个家庭的一个成员是Pitslre 蛋白激酶，p58-pitslrebeta1。 该蛋白激酶是AT之一 Pitslre家族中至少十种同工型，所有这些都表示 从染色体1p36上的三个串联连接基因跨越-90 kb。 至少三个PitsLRE激酶同工型似乎起作用 凋亡信号转导的效应因子。 染色体的p36区域 1在肿瘤发生的后期经常被删除 神经母细胞瘤以及其他肿瘤。 几个小组提出了 至少两个抑制肿瘤基因位于该染色体中 地区。 神经母细胞瘤细胞中的Pitslre基因座的研究 线表明这些基因的缺失和/或易位 在大多数具有扩增N-MYC基因的细胞系中。 此外，改变了 在几个 这些细胞系。 基于这些结果，他们提出了 N-Myc过表达提供的增殖优势发生在 凋亡信号通路已被禁用，很可能是由于 完全失活的部分或多个pitslre蛋白 激酶（S）。 突变或熄灭所涉及的蛋白质的表达 在凋亡途径中，可能是肿瘤细胞发育的关键步骤。 为了检验人类神经母细胞瘤中的这一假设，他们将执行 该提案中概述了研究。 首先，他们将确定任何 在神经母细胞瘤细胞中表达的斑点同工型中的遗传病变 线条和神经母细胞瘤患者材料。 功能属性 在此屏幕中鉴定出的Pitslre突变体的体外将分析 和体内。 其次，野生型Pitslre激酶活性将是 在含有改变斑点的同工型的神经母细胞瘤细胞中恢复 扩增的N-MYC基因。 神经母细胞瘤细胞正常的能力 斑点激酶水平和正常N-MYC水平以实验耐受 N-MYC的诱导扩增和过表达也将进行测试。 最后，受体介导的凋亡信号通路的缺陷 在其中几个 神经母细胞瘤细胞系。 他们将尝试研究这些途径 确定其缺陷的性质。 上面描述的研究 将确定单倍弥补和/或完全失活的 Pitslre激酶（S）以及N-MYC基因扩增的能力 并增强肿瘤生长是协同作用的。