Novel Pathway Connecting p53 to beta-Catenin degradation

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阻滞和在某些细胞环境中触发细胞凋亡的能力。p53诱导的G1阻滞的一种机制涉及p21 Waf1的表达，其结合并抑制活性Cdk2/Cyclin复合物。然而，最近的证据表明，存在另一种不依赖于p21waf1的途径，p53可以通过该途径抑制细胞增殖。我们已经发现了p53诱导的β -连环蛋白降解的新途径，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基因毒性损伤与b-Catenin的破坏联系起来，从而降低b-Catenin结合的Tcf/LEF转录因子的活性，并可能以p53依赖的方式促进细胞周期阻滞。本提案的目的是验证这种控制β -连环蛋白降解的新途径在体内是有效的，并且它在基因毒性损伤反应中起重要作用的假设。因此，产生了缺乏SIP的敲除小鼠，SIP是我们发现的一种蛋白质，它将p53诱导的Siam与下游靶向β -连环蛋白的蛋白质连接起来，用于泛素化和蛋白酶体依赖性降解。我们的目标是研究这些小鼠及其衍生细胞，以解决有关p53与b-连环蛋白降解途径的生物学意义和分子机制的问题。获得的结果可能为恢复在p53失活的癌症中丢失的肿瘤抑制途径提供新的策略。

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.