P53 AND ATM CHECKPOINTS IN THYMIC LYMPHOMA SUPPRESSION

胸腺淋巴瘤抑制中的 P53 和 ATM 检查点

• 批准号: 6835112
• 负责人: TERRY A VAN DYKE
• 金额: $ 36.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-04 至 2006-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6835112
• 关键词: T cell receptor; T lymphocyte; carcinogenesis; developmental genetics; gene targeting; genetic recombination; genetically modified animals; immunogenetics; laboratory mouse; leukopoiesis; loss of heterozygosity; neoplasm /cancer genetics; p53 gene /protein; thymus neoplasms

DESCRIPTION (Adapted from the Applicant's Abstract): This proposal aims to achieve a mechanistic understanding of p53 and ATM suppression in thymic lymphoma. The specific aims are: 1. Determine the mechanism by which p53 suppresses thymic lymphoma. The applicant will examine the checkpoints in stimulated p53+/+ primary thymocytes at various stages of differentiation. Tumors from p53-deficient mice will be examined for mutations in other known checkpoints. The consequences of inactivating a known mitotic checkpoint regulator, Bud 1, in vivo will be examined. 2. Determine the role of ATM in suppressing V(D)J-driven thymic lymphoma. The frequencies of interlocus recombination in ATM+/+ and +/- thymocytes and in B-cell precursors will be determined. She has already shown that interchromosoaml recombination is 10-100 fold higher than normal in ATM-/- thymocytes. She will determine whether the mechanism of ATM suppression is direct or indirect during V(D)J recombination. The impact of ATM-deficiency on cell cycle regulation of V(D)J recombination will be assessed. 3. Examine cooperation of ATM and p53 deficiencies in the development of thymic lymphoma. Tumors arising in doubly deficient mice will be analyzed for chromosomal abnormalities. Mice deficient in one gene and heterozygous for the other will be analyzed for loss of heterozygosity. Cell cycle analyses of doubly deficient thymocytes will be performed. 4. Identify oncogenic targets in ATM-deficient and p53-deficient lymphoma. Neither ATM nor p53 is sufficient to induce lymphoma; additional oncogenic events, presumably induced by translocation (ATM deficiency) or aneuploidy (p53 deficiency), are required. To determine the genes involved, differential expression analysis will be performed followed by functional analysis of candidate genes.

描述（改编自申请人摘要）：本提案旨在 实现对胸腺中p53和ATM抑制的机制理解 淋巴瘤具体目标是：1.确定p53 抑制胸腺淋巴瘤申请人将在 在不同分化阶段刺激p53+/+原代胸腺细胞。 来自p53缺陷小鼠的肿瘤将被检查其他已知的突变。 检查站使已知的有丝分裂检查点失活的后果 调节子Bud 1在体内的表达将被检查。2.确定ATM的作用 抑制V（D）J驱动的胸腺淋巴瘤。基因座间频率 ATM+/+和+/-胸腺细胞和B细胞前体中的重组将是 测定她已经证明染色体间重组是10-100 在ATM-/-胸腺细胞中比正常高10倍。她将决定是否 在V（D）J重组过程中，ATM抑制机制是直接或间接的。 ATM缺陷对V（D）J重组细胞周期调控的影响 将被评估。3.检查ATM和p53缺陷在 胸腺淋巴瘤的发展。在双缺陷小鼠中产生的肿瘤将是 进行染色体异常分析一种基因缺陷的小鼠， 对于另一个是杂合的，将分析杂合性丢失。细胞 将进行双缺陷胸腺细胞的周期分析。4.识别 ATM缺陷型和p53缺陷型淋巴瘤的致癌靶点。既不是ATM， p53足以诱导淋巴瘤;据推测， 由易位（ATM缺陷）或非整倍体（p53缺陷）诱导的， 必需的.为了确定相关基因，差异表达分析 随后进行候选基因的功能分析。