FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development.
FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development.
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DOI：
10.1016/j.canlet.2015.03.037
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发表时间：
2015-06-28
期刊：
影响因子：
9.7
通讯作者：
Lu, Jianrong
中科院分区：
文献类型：
--
作者：
Jin, Yue;Shenoy, Anitha K.;Doernberg, Samuel;Chen, Hao;Luo, Huacheng;Shen, Huangxuan;Lin, Tong;Tarrash, Miriam;Cai, Qingsong;Hu, Xin;Fiske, Ryan;Chen, Ting;Wu, Lizi;Mohammed, Kamal A.;Rottiers, Veerle;Lee, Siu Sylvia;Lu, Jianrong
Snail家族转录因子是上皮细胞向间质细胞转化（EMT）的核心诱导因子。在这里，我们表明，F-box蛋白FBXO 11识别并促进泛素介导的多个蜗牛家族成员，包括划痕降解。FBXO 11和Snai 1之间的关联在体外是独立的Snai 1磷酸化。FBXO 11在间充质细胞中的过表达降低了Snail蛋白丰度和细胞侵袭力。相反，上皮癌细胞中内源性FBXO 11的耗尽导致Snail蛋白积累、EMT和肿瘤侵袭，以及乳腺癌细胞中雌激素受体表达的丧失。EMT诱导信号TGFβ和镍下调FBXO 11的表达。在人类癌症中，高FBXO 11水平与上皮标志物的表达和良好的预后相关。结果表明，FBXO 11维持上皮状态并抑制癌症进展。FBXO 11在小鼠中的失活导致新生儿死亡、表皮增厚和表皮中Snail蛋白水平增加，证实FBXO 11是Snail的生理性泛素连接酶。此外，在C.在线虫中，FBXO 11突变体表型归因于Snail因子，因为它被Snail同源物的失活/耗尽抑制。总的来说，这些发现表明FBXO 11-Snail调节轴在进化上是保守的，并且关键地控制癌进展和哺乳动物表皮发育。
The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.
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TGFβ 信号的背景
DOI：
10.1038/nrm3434
发表时间：
2012-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
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