Adenomatous polyposis coli (APC)-independent regulation of β-catenin degradation via a retinoid X receptor-mediated pathway
Adenomatous polyposis coli (APC)-independent regulation of β-catenin degradation via a retinoid X receptor-mediated pathway
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DOI：
10.1074/jbc.m304761200
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发表时间：
2003-08-08
影响因子：
4.8
通讯作者：
Chandraratna, RAS
中科院分区：
文献类型：
--
作者：
Xiao, JH;Ghosn, C;Chandraratna, RAS
β-连环蛋白是稳定的细胞粘附复合物的组分，而其游离形式作为转录因子发挥作用，调节与肿瘤发生和转移有关的基因。游离β-连环蛋白通过两种腺瘤性结肠息肉病（APC）依赖性蛋白酶体降解途径消除，这两种途径由糖原合成酶激酶3 β（GSK 3 β）或p53诱导型Siah-1调节。APC依赖性途径的关键基因突变导致的β-连环蛋白周转失调与癌症如结肠直肠癌有关。我们已经确定了一种新的类维生素A X受体（RXR）介导的APC非依赖性途径的β-连环蛋白的调节。在该蛋白酶体途径中，RXR激动剂诱导β-连环蛋白和RXR α的降解并抑制β-连环蛋白介导的转录。在体内，β-连环蛋白与RXR α相互作用的配体的情况下，但RXR激动剂增强的相互作用。RXR激动剂作用不受GSK 3 β抑制剂或β-连环蛋白中GSK 3 β靶向序列缺失的影响。在APC和p53突变的结直肠癌细胞中，RXR激动剂仍然通过RXR α使内源性β-连环蛋白失活。有趣的是，RXR α A/B区的缺失消除了配体诱导的β-连环蛋白降解，但没有消除RXR α介导的反式激活。RXRa介导的致癌β-连环蛋白失活降低了细胞增殖。这些结果表明RXR及其激动剂在β-连环蛋白周转和相关生物学事件的调节中具有潜在作用。
beta-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free beta-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3beta (GSK3beta) or p53-inducible Siah-1. Dysregulation of beta-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of beta-catenin. In this proteasomal pathway, RXR agonists induce degradation of beta-catenin and RXRalpha and repress beta-catenin-mediated transcription. In vivo, beta-catenin interacts with RXRalpha in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3beta inhibitors or deletion of the GSK3beta-targeted sequence from beta-catenin. In APC- and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous beta-catenin via RXRalpha. Interestingly, deletion of the RXRalpha A/B region abolished ligand-induced beta-catenin degradation but not RXRalpha-mediated transactivation. RXRalpha-mediated inactivation of oncogenic beta-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of beta-catenin turnover and related biological events.