Oestrogen causes degradation of KLF5 by inducing the E3 ubiquitin ligase EFP in ER-positive breast cancer cells.
Oestrogen causes degradation of KLF5 by inducing the E3 ubiquitin ligase EFP in ER-positive breast cancer cells.
复制标题
DOI：
10.1042/bj20101388
复制
发表时间：
2011-07-15
期刊：
影响因子：
--
通讯作者：
Dong JT
中科院分区：
文献类型：
--
作者：
Zhao KW;Sikriwal D;Dong X;Guo P;Sun X;Dong JT
Krüppel样因子5（KLF 5）是一种多功能转录因子，参与细胞增殖、分化和癌变过程。除了在不同类型的人类癌症（包括乳腺癌）中频繁失活外，KLF 5已被鉴定为TGF-β肿瘤抑制因子的重要辅助因子。在我们之前的研究中，我们发现KLF 5对乳腺癌细胞中ER（雌激素受体α）功能具有负调节作用，我们注意到雌激素降低了KLF 5的蛋白水平。在这项研究中，我们测试了雌激素-ER信号是否以及如何调节KLF 5蛋白。我们发现雌激素引起KLF 5蛋白的降解，并且这种降解对蛋白酶体抑制剂敏感，而对其他抑制剂不敏感。雌激素诱导的E3连接酶EFP被鉴定为雌激素介导的KLF 5降解的关键参与者，因为EFP的敲低和过表达分别增加和降低KLF 5蛋白水平，并且即使蛋白质合成被阻断，这种降低仍在继续。EFP介导的降解损害了KLF 5在基因转录中的功能。虽然只有未泛素化的EFP与KLF 5相互作用，但EFP的过表达似乎阻止了KLF 5的泛素化，同时导致E3本身的重泛素化。此外，泛素化的EFP中断其与KLF 5的相互作用。虽然EFP如何降解KLF 5的机制仍有待确定，但这些结果表明，雌激素通过诱导ER阳性乳腺癌细胞中EFP的表达而导致KLF 5蛋白的降解。
Krüppel-like factor 5 (KLF5) is a multifunctional transcription factor involved in cell proliferation, differentiation and carcinogenesis. In addition to frequent inactivation in different types of human cancers including breast cancer, KLF5 has been identified as an essential co-factor for the TGF-β tumor suppressor. In our previous study demonstrating a negative regulation of ER (estrogen receptor alpha) function by KLF5 in breast cancer cells, we noticed that estrogen reduced the protein level of KLF5. In this study, we tested whether and how estrogen-ER signaling regulates KLF5 protein. We found that estrogen caused the degradation of KLF5 protein, and the degradation was sensitive to proteasome inhibitors but not other inhibitors. The estrogen-inducible E3 ligase EFP was identified as a key player in estrogen-mediated degradation of KLF5, as knockdown and over-expression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked. EFP-mediated degradation impaired the function of KLF5 in gene transcription. While only unubiquitinated EFP interacted with KLF5, overexpression of EFP appeared to prevent the ubiquitination of KLF5 while resulting in heavy ubiquitination of the E3 itself. Furthermore, ubiquitination of EFP interrupted its interaction with KLF5. Although the mechanism for how EFP degrades KLF5 remains to be determined, these results suggest that estrogen causes the degradation of KLF5 protein by inducing the expression of EFP in ER-positive breast cancer cells.