Positive reciprocal regulation of ubiquitin C-terminal hydrolase L1 and beta-catenin/TCF signaling.
Positive reciprocal regulation of ubiquitin C-terminal hydrolase L1 and beta-catenin/TCF signaling.
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DOI：
10.1371/journal.pone.0005955
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发表时间：
2009-06-18
期刊：
影响因子：
3.7
通讯作者：
Shackelford J
中科院分区：
文献类型：
--
作者：
Bheda A;Yue W;Gullapalli A;Whitehurst C;Liu R;Pagano JS;Shackelford J
去泛素化酶（DUBs）参与不同的关键细胞过程的调节。泛素C末端水解酶L1（UCH L1）与多种神经系统疾病和人类癌症有关，但其生理靶点和体内表达调控在很大程度上尚未探索。在这里，我们证明了UCH L1上调β-catenin/TCF信号传导：UCH L1与β-catenin形成内源性复合物，稳定它并上调β-catenin/TCF依赖性转录。我们还发现，β-catenin/TCF信号上调内源性UCH L1 mRNA和蛋白的表达。此外，使用ChIP测定和直接诱变，我们确定了两个TCF 4-结合位点的UCH L1启动子参与这种调节。由于UCH L1的表达和去泛素化活性是其自身基本启动子活性所必需的，因此我们认为UCH L1通过激活转化细胞中的致癌β-catenin/TCF信号来上调其表达。
Deubiquitinating enzymes (DUBs) are involved in the regulation of distinct critical cellular processes. Ubiquitin C-terminal Hydrolase L1 (UCH L1) has been linked to several neurological diseases as well as human cancer, but the physiological targets and the regulation of UCH L1 expression in vivo have been largely unexplored. Here we demonstrate that UCH L1 up-regulates β-catenin/TCF signaling: UCH L1 forms endogenous complexes with β-catenin, stabilizes it and up-regulates β-catenin/TCF-dependent transcription. We also show that, reciprocally, β-catenin/TCF signaling up-regulates expression of endogenous UCH L1 mRNA and protein. Moreover, using ChIP assay and direct mutagenesis we identify two TCF4-binding sites on the uch l1 promoter that are involved in this regulation. Since the expression and deubiquitinating activity of UCH L1 are required for its own basic promoter activity, we propose that UCH L1 up-regulates its expression by activation of the oncogenic β-catenin/TCF signaling in transformed cells.
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