Crosstalk of EDA-A2/XEDAR in the p53 Signaling Pathway
Crosstalk of EDA-A2/XEDAR in the p53 Signaling Pathway
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DOI：
10.1158/1541-7786.mcr-09-0484
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发表时间：
2010-06-01
影响因子：
5.2
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Tanikawa, Chizu;Ri, Cui;Matsuda, Koichi
我们最近确定X连锁外胚层发育不良受体（XEDAR，也称为TNFRSF 27或EDA 2 R）作为直接p53靶点，由于其表观遗传学改变或通过p53基因突变，在结直肠癌组织中经常下调。然而，XEDAR蛋白的翻译后调节在结直肠癌发生中的作用至今尚未完全阐明。在这里，我们报告，XEDAR蛋白的细胞外NH 2末端被金属蛋白酶切割并释放到培养基中。剩余的羧基末端膜锚定片段通过泛素-蛋白酶体途径迅速降解。有趣的是，异位p53表达也反式激活XEDAR配体EDA-A2和XEDAR。此外，EDA-A2阻断XEDAR的切割，随后抑制细胞生长。我们还在NCI-H716结直肠癌细胞中发现了XEDAR基因的错义突变，该突变导致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XEDAR的生理功能至关重要。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。Mol Cancer Res; 8（6）; 855-63. (C)2010年AACR。
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 NH2 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. Mol Cancer Res; 8(6); 855-63. (C) 2010 AACR.