Cancer Susceptibility and MSI Analyses of Mlh3 Null Mice

Mlh3 无效小鼠的癌症易感性和 MSI 分析

• 批准号: 7896180
• 负责人: Steven M Lipkin
• 金额: $ 3.49万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896180
• 关键词: Address; Apoptosis; Brain; Cancer Etiology; Cancerous; Carcinogenesis Mechanism; Cell Death; Cells; DNA; DNA Damage; Defect; Endometrial Carcinoma; Endometrium; Epithelial Cells; Event; Failure; Frameshift Mutation; Frequencies; Gene Mutation; Hereditary Nonpolyposis Colorectal Neoplasms; In Vitro; Inherited; Intestinal Cancer; Intestines; Kidney; Knockout Mice; Malignant Neoplasms; Mediating; Meiosis; Microsatellite Instability; Mismatch Repair; Mus; Mutate; Mutation; Ovary; PMS2 gene; Patients; Personal Communication; Phenotype; Pongidae; Predisposition; Rate; Research Personnel; Small Intestines; Stomach; Sweden; Syndrome; Testing; Tumor Suppressor Genes; Universities; adenoma; cancer genetics; cancer type; carcinogenesis; design; in vivo; insertion/deletion mutation; programs; repaired; response; tumor

DESCRIPTION (provided by applicant): Defective DNA mismatch repair (MMR) causes cancer. MMR mutations use multiple distinct mechanisms to cause cancer: (A) Defective repair of insertion/deletion frameshift mutations (commonly called Microsatellite Instability or MSI), (B) Defective repair of single-basepair DNA mismatches, and (C) Failure to initiate apoptosis in response to DNA damage. Previously, I cloned MLH3. Both inherited and sporadic MLH3 mutations cause CRC and perhaps other types of cancer as well. Gerrnline and sporadic MLH3 mutations are associated with both MSI v and MSI- CRCs. In mice, Mlh3 is essential for meiosis. New results from my lab demonstrate Mlh3 -/- and Mlh3-/-/Pms2-/- mice develop multiple types of cancer, including bowel cancer. However, studies to date have not addressed critical questions: What are the mechanisms of carcinogenesis in cells with MLH3 mutations? What are the mechanisms of carcinogenesis in cells with both MLH3 and PMS2 mutations? We therefore propose the following Aims: Specific Aim 1: To Identify the Mechanisms of Apc Inactivation in Mlh3 -/- and Mlh3-/- Pms2-/- Bowel Cancers. These mechanisms are important to determine because MLH3 and PMS2 mutations underlie both inherited and sporadic forms of CRC in patients. Specific Aim 2: To Analyze Mlh3 -/- Cells for Defects in DNA Damage Induced Apoptosis as a Potential Mechanism of Carcinogenesis. This aim tests the hypothesis that Mlh3 -/- cells do not correctly initiate apoptosis in response to DNA damage as a potential mechanism of carcinogenesis. Specific Aim 3: To Determine Insertion/Deletion MSI and Single-Basepair Mismatch Repair Phenotypes of Mlh3 -/-cells in vitro and in rive as potential mechanisms of carcinogenesis. The aim tests two hypotheses: (1) Mlh3 mutations cause MSI and (2) Mlh3 mutations disrupt single-basepair mismatch repair.

描述（由申请人提供）：DNA错配修复缺陷（MMR）导致癌症。MMR突变使用多种不同的机制导致癌症：(A)插入/删除移码突变的修复缺陷（通常称为微卫星不稳定性或MSI）， (B)单碱基对DNA错配的修复缺陷，以及(C)响应DNA损伤时未能启动细胞凋亡。