Beta-catenin regulation by tumor suppressor APC

抑癌基因 APC 对 β-连环蛋白的调节

• 批准号: 7001272
• 负责人: CHUNMING LIU
• 金额: $ 13.27万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7001272
• 关键词: RNA interference; biological signal transduction; cadherins; colon neoplasms; gene induction /repression; genetic regulation; neoplastic cell; phosphorylation; protein degradation; protein structure function; tissue /cell culture; tumor suppressor proteins; ubiquitin

DESCRIPTION (provided by applicant): Colorectal cancer is the third leading cause of cancer-related deaths in the United States with 130,000 new cases diagnosed per year and approximately 57,000 deaths expected in 2004. A better understanding of the signaling pathways contributing to colorectal cancer progression will provide targets for novel therapeutic agents to treat this disease. Approximately 85% of colorectal cancers have mutations of the APC (adenomatous polyposis coil) tumor suppressor gene, and about 13% of colorectal cancers have mutations of the B-catenin oncogene. Mutations in APC genes result in B-catenin accumulation that activates other oncogenes. B-catenin stability is controlled by N-terminal serine/threonine phosphorylation. The phosphorylated B-catenin is degraded by the ubiquitin/proteasome pathway. B-catenin mutations that escape phosphorylation or ubiquitination result in abnormal B-catenin accumulation that lead to cancer. Conversely, the molecular mechanisms of APC mediated B-catenin degradation are not clear. Most APC mutations in colon cancers are C-terminal truncations; APC truncations missing different functional domains result in varying levels of tumor differentiation. The central hypothesis of this proposal is that APC regulates B-catenin degradation by regulating both B-catenin phosphorylation and ubiquitination. To examine our hypothesis, we have designed experiments with the following Specific Aims: 1) to delineate mechanisms of APC mediated regulation of B-catenin phosphorylation, and 2) to assess the mechanisms contributing to APC regulation of B-catenin ubiquitination. B-catenin phosphorylation and ubiquitination are regulated by distinct domains of APC. Understanding these regulations at a molecular level is crucial for rational drug design for colon cancer therapeutics.

描述（由申请人提供）：结直肠癌是美国与癌症相关死亡的第三大主要原因，每年诊断为130,000例新病例，预计在2004年预计约57,000例死亡。更好地了解有助于结直肠癌进展的信号传导途径将为治疗这种疾病提供新的治疗药物。大约85％的结直肠癌具有APC的突变（腺瘤性息肉线圈）抑制基因，约有13％的结直肠癌具有B-catenin癌的突变。 APC基因中的突变导致B-catenin的积累，从而激活其他癌基因。 B-连环蛋白的稳定性受N末端丝氨酸/苏氨酸磷酸化的控制。磷酸化的B-catenin被泛素/蛋白酶体途径降解。避免磷酸化或泛素化的B-连环蛋白突变会导致异常的B-catenin积累导致癌症。相反，APC介导的B-catenin降解的分子机制尚不清楚。结肠癌中的大多数APC突变是C末端截断。 APC截断缺少不同的功能域导致肿瘤分化水平的不同。该提案的中心假设是APC通过调节B-钙蛋白磷酸化和泛素化来调节B-catenin降解。为了审查我们的假设，我们设计了以下特定目的的实验：1）描述APC介导的B-catenin磷酸化调节机制，以及2）评估有助于B-catenin泛素化的APC调节的机制。 B-catenin磷酸化和泛素化受APC的不同域调节。在分子水平上了解这些法规对于结肠癌疗法的合理药物设计至关重要。