Novel Pathway Connecting p53 to beta-Catenin degradation

连接 p53 与 β-Catenin 降解的新途径

• 批准号: 6764813
• 负责人: SHU-ICHI MATSUZAWA
• 金额: $ 17.28万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764813
• 关键词: DNA damage; apoptosis; binding proteins; biological signal transduction; cadherins; cell cycle; cell growth regulation; cell proliferation; flow cytometry; gene expression; gene mutation; genetically modified animals; immunocytochemistry; laboratory mouse; laboratory rabbit; p53 gene /protein; protein binding; protein degradation; protein metabolism; protein protein interaction; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The tumor suppressor p53 has multiple functions in cells, including an ability to induce cell cycle arrest in essentially all types of cells and to trigger apoptosis in some cellular contexts. One mechanism of p53- induced G1 arrest involves expression of p21 Waf1, which binds and inhibits active Cdk2/Cyclin complexes. However, recent evidence suggests the existence of an alternative p21Waf1-independent pathway through which p53 can suppress cell proliferation. We have discovered a novel pathway for p53-induced beta-Catenin degradation involving Siah and Ebi, a F-box protein which binds beta-Catenin (Matsuzawa & Reed. Mol Cell 7:915,2001). A series of protein interactions link genotoxic injury to destruction of b-Catenin, thus reducing activity of b-Catenin-binding Tcf/LEF transcription factors and potentially contributing to cell cycle arrest in a p53-dependent manner. The goal of this proposal is to test the hypothesis that this novel pathway for controlling beta-Catenin degradation is operative in vivo and that it plays an important role in genotoxic injury responses. Accordingly, knock-out mice have been generated which lack SIP, a protein we identified that bridges p53-inducible Siam to downstream proteins targeting beta-Catenin for ubiquitination and proteasome dependent degradation. Our goals are to study these mice and cells derived from them for addressing questions about the biological significance and molecular mechanisms of this pathway which links p53 to b-Catenin degradation. The results obtained could suggest new strategies for restoring tumor suppressive pathways lost in cancers that have suffered p53 inactivation.

描述（由申请人提供）：肿瘤抑制因子p53在细胞中具有多种功能，包括在基本上所有类型的细胞中诱导细胞周期停滞和在某些细胞环境中触发细胞凋亡的能力。p53诱导的G1期阻滞的一种机制涉及p21 Waf 1的表达，其结合并抑制活性Cdk 2/细胞周期蛋白复合物。 然而，最近的证据表明，存在一个替代的p21 Waf 1非依赖性途径，通过该途径p53可以抑制细胞增殖。我们已经发现了p53诱导的β-连环蛋白降解的新途径，其涉及Siah和Ebi，一种结合β-连环蛋白的F-box蛋白（Matsuzawa & Reed. Mol Cell 7：915，2001）。 一系列蛋白质相互作用将遗传毒性损伤与b-连环蛋白的破坏联系起来，从而降低了b-连环蛋白结合Tcf/LEF转录因子的活性，并可能以p53依赖的方式导致细胞周期停滞。该提案的目的是检验这一假说，即控制β-连环蛋白降解的新途径在体内是有效的，并且在遗传毒性损伤反应中起重要作用。 因此，已经产生了缺乏SIP的敲除小鼠，SIP是我们鉴定的将p53诱导型Siam与靶向β-连环蛋白的下游蛋白质桥接以进行泛素化和蛋白酶体依赖性降解的蛋白质。 我们的目标是研究这些小鼠和来自它们的细胞，以解决有关p53与b-连环蛋白降解之间的生物学意义和分子机制的问题。 所获得的结果可能为恢复在遭受p53失活的癌症中丢失的肿瘤抑制途径提供新的策略。