Role of p53 Missense Mutations on Tumorigenesis in Vivo

描述（由申请人提供）：p53基因本身或p53途径的其他重要组分在大多数人类癌症的发生中发生改变。响应于DNA损伤信号或不适当的癌基因激活，p53水平增加并导致细胞周期停滞或诱导凋亡，p53监视因此防止不适当的DNA复制和细胞分裂。大多数研究都集中在了解p53的凋亡机制，而p53诱导细胞周期阻滞程序的能力在很大程度上被忽视。在上一个资助期间，我们产生了一只小鼠，该小鼠在p53氨基酸172处含有arg-to-pro突变，这可以区分这些途径。p53（515 c）等位基因纯合的细胞不能诱导凋亡，但保留部分细胞周期阻滞途径。淋巴瘤和肉瘤在p53（515 c）纯合子小鼠中发展，其潜伏期比p53缺失小鼠晚得多，表明细胞周期阻滞在肿瘤抑制中的重要性。重要的是，在p53（515 c）/（515 c）小鼠中发展的肿瘤保持二倍体，表明这种突变型p53的活性保持基因组稳定性。这些小鼠和来自这些小鼠的细胞的产生将使我们能够破译基因组稳定性的机制以及该途径在具有其他分子缺陷的肿瘤发生中的重要性。具体而言，我们将：1）确定在肿瘤发生中与p53（515 c）/（515 c）协同作用的分子变化; 2）检查来自p53（515 c）/-小鼠的肿瘤中的存活率和基因组稳定性; 3）确定细胞周期抑制剂和p53靶点p21在维持基因组稳定性中的重要性，并鉴定在阻止细胞周期中重要的p53的其他靶点; 4）确定p53（515 c）/（515 c）突变体抑制c-myc诱导的肿瘤的能力;和5）确定p53（515 c）/（515 c）在不同的肿瘤倾向小鼠品系中延迟乳腺癌的重要性。这种独特的模型将进一步加深我们对p53在细胞周期阻滞和维持基因组稳定性中的作用的理解。

DESCRIPTION (provided by applicant): The p53 gene itself or other important components of the p53 pathway are altered in the genesis of most human cancers. In response to DNA damage signals or inappropriate oncogene activation, p53 levels increase and result in arrest of the cell cycle or induction of apoptosis, p53 surveillance thus prevents inappropriate DNA replication and cell division. Most studies have focused on understanding the mechanisms of apoptosis by p53 while the ability of p53 to induce the cell cycle arrest program has largely been ignored. During the previous funding period, we generated a mouse containing an arg-to-pro mutation at p53 amino acid 172, which distinguishes these pathways. Cells homozygous for the p53(515c) allele are unable to induce apoptosis, yet retain a partial cell cycle arrest pathway. Lymphomas and sarcomas develop in p53(515c) homozygous mice with much later latency than p53-null mice suggesting the importance of cell cycle arrest in tumor suppression. Importantly, tumors that develop in p53(515c)/(515c) mice remain diploid suggesting that the activities of this mutant p53 maintain genomic stability. The generation of these mice and cells from these mice will allow us to decipher the mechanism of genomic stability and the importance of this pathway in the genesis of tumors with other molecular defects. Specifically we will: 1) determine the molecular changes that cooperate with p53(515c)/(515c) in tumorigenesis; 2) examine survival and genomic stability in tumors from p53(515c)/- mice; 3) determine the importance of the cell cycle inhibitor and p53 target p21 in maintaining genomic stability and identify other targets of p53 important in arresting the cell cycle; 4) determine the ability of p53(515c)/(515c) mutant to inhibit c-myc induced tumors; and 5) determine the importance of p53(515c)/(515c) in delaying breast carcinomas in a different tumor prone strain of mice. This unique model will further our understanding of the role of p53 in cell cycle arrest and in maintaining genome stability.