Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato, Tokyo 1088639, Japan.
Mol Cancer Res. 2010 Jun;8(6):855-63. doi: 10.1158/1541-7786.MCR-09-0484. Epub 2010 May 25.
We recently identified X-linked ectodermal dysplasia receptor (XEDAR, also known as TNFRSF27 or EDA2R) as a direct p53 target that was frequently downregulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. However, the role of the posttranslational regulation of XEDAR protein in colorectal carcinogenesis was not well clarified thus far. Here, we report that the extracellular NH(2) terminus of XEDAR protein was cleaved by a metalloproteinase and released into culture media. The remaining COOH-terminal membrane-anchored fragment was rapidly degraded through the ubiquitin-proteasome pathway. Interestingly, ectopic p53 expression also transactivated an XEDAR ligand, EDA-A2, together with XEDAR. Moreover, EDA-A2 blocked the cleavage of XEDAR and subsequently inhibited cell growth. We also found a missense mutation of the XEDAR gene in NCI-H716 colorectal cancer cells, which caused the translocation of XEDAR protein from cell membrane to cytoplasm. This mutation attenuated the growth-suppressive effect of XEDAR, indicating that membrane localization is critical for physiologic XEDAR function. Thus, our findings clearly revealed the crucial role of EDA-A2/XEDAR interaction in the p53-signaling pathway.
我们最近发现 X 连锁外胚层发育不良受体（XEDAR，也称为 TNFRSF27 或 EDA2R）是 p53 的直接靶标，由于其表观遗传改变或通过 p53 基因突变，在结直肠癌细胞组织中经常下调。然而，XEDAR 蛋白的翻译后调节在结直肠发生中的作用迄今尚未阐明。在这里，我们报告 XEDAR 蛋白的细胞外 NH2 端被金属蛋白酶切割，并释放到培养基中。剩余的 COOH 端膜锚定的片段通过泛素-蛋白酶体途径迅速降解。有趣的是，外源性 p53 表达也可与 XEDAR 一起反式激活 XEDAR 配体 EDA-A2。此外，EDA-A2 阻断了 XEDAR 的切割，随后抑制了细胞生长。我们还在 NCI-H716 结直肠癌细胞中发现了 XEDAR 基因的错义突变，导致 XEDAR 蛋白从细胞膜易位到细胞质。这种突变减弱了 XEDAR 的生长抑制作用，表明膜定位对于生理 XEDAR 功能至关重要。因此，我们的研究结果清楚地揭示了 EDA-A2/XEDAR 相互作用在 p53 信号通路中的关键作用。
