Mouse Models for Li Fraumeni Syndrome

Li Fraumeni 综合征小鼠模型

• 批准号: 7822818
• 负责人: GUILLERMINA LOZANO
• 金额: $ 32.47万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7822818
• 关键词: Address; Alleles; Amino Acids; Arginine; Binding; Carcinoma; Cell Culture Techniques; Cell Cycle Regulation; Cells; Conflict (Psychology); Coupled; DNA; DNA Binding Domain; Data; Defect; Development; Dominant-Negative Mutation; Event; Exhibits; Family; Generations; Genetic; Growth; Hot Spot; Human; In Vitro; Individual; Inherited; Li-Fraumeni Syndrome; Loss of Heterozygosity; Malignant Childhood Neoplasm; Malignant Neoplasms; Missense Mutation; Modeling; Molecular; Molecular Conformation; Mus; Mutant Strains Mice; Mutation; Nature; Neoplasm Metastasis; Nonsense Mutation; Normal Cell; Normal tissue morphology; Nucleotides; Other Genetics; Pathway interactions; Patients; Phenotype; Predisposition; Prevalence; Principal Investigator; Property; Protein p53; Proteins; Public Health; Research; Role; System; TP53 gene; Testing; Tumor Cell Line; gain of function; immortalized cell; in vivo; in vivo Model; insight; malignant breast neoplasm; mouse model; mutant; new therapeutic target; overexpression; programs; research study; sarcoma; tumor; tumorigenesis; tumorigenic

Mutation of p53, inherited in some individuals with Li-Fraumeni syndrome (LFS), is a critical event in the elaboration of many tumors of diverse origin. Most mutations of p53 are single nucleotide changes that alter critical amino acids in the DNA-binding domain rather than alterations that delete the p53 gene. The prevalence of p53 missense mutations coupled with in vitro data has led to the hypothesis that mutant p53 has additional properties that make it more detrimental for proper cell cycle regulation and more advantageous to the dividing cell. To test this hypothesis in vivo and model human LFS more accurately, we have generated mouse models inheriting the p53R172H mutation (corresponding to the p53R175H hotspot in human cancers). This mutation disrupts the conformation of p53 resulting in a protein that is tumorigenic in cooperation with ras, and readily immortalizes cells. Mice with the p53R172H mutation have gained additional tumorigenic properties and also exhibit a dominant-negative phenotype. Metastasis is rampant in p53R172H/+ mice as opposed to mice lacking one p53 allele. Additional experiments are needed to ascertain the events leading to tumorigenesis, metastasis, stability of the mutant p53, and the dominantnegative nature of the mutation. To examine the ability of p53R172H to cooperate with Brcal deletion, another common alteration that leads to breast cancer, crosses with Brca1+/- mice in a background sensitive to beast cancer will be performed. An important question that will be addressed in these studies is what other molecular changes, examined by CGH and Affymetric arrays, cooperate with mutant p53 in the genesis of different kinds of cancers. Lastly, since the type of p53 missense mutation may also contribute to different phenotypes, another p53 missense mutation will be generated in mice. The p53R245W mutation represents a DMA contact mutant that alters an arginine amino acid involved in direct contact to DNA. p53R245W is also transcriptionally inactive, but cannot immortalize cells. The p53R245W mutation in another hot spot mutation inherited in LFS patients. Comparison of the two classes of p53 mutants (conformation versus contact) should yield insights into the role of these mutants in tumorigenesis. Our studies suggest that treatment of a patient will have to be tailored not only to the kind of tumor that develops, but to the specific p53 missense mutation identified in the tumor as well. The research outlined in this application is directly relevant to public health in that it proposes to study a gene, p53, that is often altered in different kinds of cancers. The study aims to understand the nature of p53 mutations and of other changes that cooperate with this defect. These studies may identify novel therapeutic targets.

p53突变，某些患有Li-Fraumeni综合征（LFS）的个体，是一个关键事件 阐述许多起源的肿瘤。 p53的大多数突变是改变的单核苷酸变化 DNA结合结构域中的临界氨基酸，而不是删除p53基因的改变。这 p53错义突变的患病率与体外数据相结合，导致了突变体p53的假设 具有其他特性，使其对适当的细胞周期调节更有害，并且更多 有利于分隔的单元格。为了更准确地在体内检验这一假设，我们 已经生成了遗传p53R172H突变的鼠标模型（对应于p53r175h热点 在人类癌症中）。这种突变破坏了p53的构象，导致蛋白质在 与RAS合作，很容易使细胞永生。 p53R172H突变的小鼠已获得 额外的肿瘤性特性，也表现出显性阴性表型。转移猖ramp p53r172h/+小鼠与缺少一个p53等位基因的小鼠相反。需要其他实验 确定导致肿瘤发生，转移，突变体p53的稳定性的事件和显性不受限制的事件 突变的性质。要检查p53r172h与BRCAL缺失合作的能力， 导致乳腺癌的另一个常见改变，与BRCA1 +/-小鼠交叉 将对野兽癌敏感。这些研究将要解决的一个重要问题是 CGH和Affymetric阵列检查的其他分子变化，与突变体p53合作 各种癌症的起源。最后，由于p53错义突变的类型也可能有助于 不同的表型，将在小鼠中产生另一种p53错义突变。 p53R245W突变 代表一种DMA接触突变体，该突变体改变了与DNA直接接触的精氨酸氨基酸。 p53R245W在转录上也无活性，但不能使细胞永生。 p53R245W突变 LFS患者继承的另一个热点突变。比较两类p53突变体 （构象与接触）应对这些突变体在肿瘤发生中的作用产生见解。我们的 研究表明，患者的治疗不仅必须针对发生的肿瘤，还必须量身定制 但是对于在肿瘤中发现的特定p53错义突变。 本应用程序中概述的研究与公共卫生直接相关，它建议研究 基因，p53，通常会在不同种类的癌症中改变。该研究旨在了解p53的性质 突变和其他与此缺陷合作的变化。这些研究可能鉴定出新的治疗性 目标。