Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA.
Department of Oral Health Sciences and Centre for Oral Health Research, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.
Nat Commun. 2017 Nov 16;8(1):1534. doi: 10.1038/s41467-017-01199-8.
The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCF complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCF. Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations. Critically, in head and neck squamous cell carcinoma, Fxr1 overexpression correlates with reduced Fbxo4 levels in the absence of mutations or loss of mRNA, suggesting the potential for feedback regulation. Direct analysis reveals that Fbxo4 translation is attenuated by Fxr1, indicating the existence of a feedback loop that contributes to Fxr1 overexpression and the loss of Fbxo4. Ultimately, the consequence of Fxr1 overexpression is the bypass of senescence and neoplastic progression.
Fbxo4 肿瘤抑制因子是 Skp1-Cul1-F-box E3 连接酶的一个组成部分，已知有两种底物。在这里，我们展示了 SCF 复合物的纯化导致脆性 X 蛋白家族（FMRP、Fxr1 和 Fxr2）作为结合伴侣被鉴定出来。生化和功能分析表明，Fxr1 是 SCF 的直接底物。与底物关系一致，Fxr1 在 Fbxo4 敲除细胞、组织和携带失活 Fbxo4 突变的人类癌细胞中过度表达。至关重要的是，在头颈部鳞状细胞癌中，Fxr1 的过表达与 Fbxo4 水平的降低相关，而没有突变或 mRNA 丢失，这表明存在潜在的反馈调节。直接分析表明，Fxr1 会削弱 Fbxo4 的翻译，这表明存在一个反馈回路，有助于 Fxr1 的过表达和 Fbxo4 的丢失。最终，Fxr1 过表达的结果是绕过衰老和肿瘤进展。
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