Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells
Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells
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DOI：
10.1074/jbc.m506183200
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发表时间：
2005-12-16
影响因子：
4.8
通讯作者：
Dong, JT
中科院分区：
文献类型：
--
作者：
Chen, CS;Sun, XD;Dong, JT
转录因子KLF 5在人类肿瘤发生中起重要作用。在上皮细胞中，KLF 5蛋白受到泛素-蛋白酶体途径的严格调控。为了更好地理解KLF 5蛋白的调节机制，我们鉴定并表征了KLF 5的E3泛素连接酶，即WWP 1。我们发现WWP 1在体内和体外与KLF 5形成蛋白复合物。此外，WWP 1介导了KLF 5的泛素化和降解，并且WWP 1的催化半胱氨酸残基对其功能至关重要。KLF 5的反式激活结构域中的PY基序是其与WWP 1相互作用所必需的。最后，WWP 1在前列腺和乳腺癌细胞系中扩增并过表达，负调控KLF 5的基因调控功能。这些发现不仅确立了WWP 1作为KLF 5的E3泛素连接酶，还进一步暗示了KLF 5通路在人类致癌中的作用。
The transcription factor KLF5 plays an important role in human carcinogenesis. In epithelial cells, the KLF5 protein is tightly regulated by the ubiquitin-proteasome pathway. To better understand the mechanisms for the regulation of KLF5 protein, we identified and characterized an E3 ubiquitin ligase for KLF5, i.e. WWP1. We found that WWP1 formed a protein complex with KLF5 in vivo and in vitro. Furthermore, WWP1 mediated the ubiquitination and degradation of KLF5, and the catalytic cysteine residue of WWP1 is essential for its function. A PY motif in a transactivation domain of KLF5 is necessary for its interaction with WWP1. Finally, WWP1 was amplified and overexpressed in some cancer cell lines from the prostate and breast, which negatively regulated the function of KLF5 in gene regulation. These findings not only established WWP1 as an E3 ubiquitin ligase for KLF5, they also further implicated the KLF5 pathway in human carcinogenesis.