P53 AND ATM CHECKPOINTS IN THYMIC LYMPHOMA SUPPRESSION

描述(改编自申请人的摘要)：本提案旨在 实现对胸腺中P53和ATM抑制的机制理解 淋巴瘤。其具体目的是：1.确定P53的作用机制 抑制胸腺淋巴瘤。申请者将检查检查站在 刺激不同分化阶段的P53+/+原代胸腺细胞。 来自p53基因缺陷小鼠的肿瘤将被检查其他已知的突变 检查站。停用已知的有丝分裂检查点的后果 调节剂，芽1，活体将被检查。2.确定自动柜员机在 抑制V(D)J驱动的胸腺淋巴瘤。基因座间的频率 ATM+/+和+/-胸腺细胞和B细胞前体细胞的重组将是 下定决心。她已经证明染色体间重组率为10-100。 ATM-/-胸腺细胞的倍数高于正常。她将决定是否 在V(D)J复合过程中，ATM的抑制机制是直接或间接的。 ATM缺乏对V(D)J重组细胞周期调控的影响 将会被评估。3.考察ATM和P53在合作中的不足 胸腺淋巴瘤的发展。在双缺陷小鼠中产生的肿瘤将是 对染色体异常进行分析。一种基因缺陷的小鼠 对于另一种杂合子，将分析杂合性丢失。细胞 将对双缺陷胸腺细胞进行周期分析。4.识别 ATM基因缺陷和P53基因缺陷淋巴瘤的致癌靶点。既不是自动取款机也不是 P53足以诱发淋巴瘤；推测还有其他致癌事件 由易位(ATM缺乏症)或非整倍体(P53缺乏症)引起的 必填项。为了确定涉及的基因，差异表达分析 随后将进行候选基因的功能分析。

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.