Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation.
Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation.
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DOI：
10.1038/s41598-017-12675-y
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发表时间：
2017-10-02
影响因子：
4.6
通讯作者：
Kobayashi A
中科院分区：
文献类型：
--
作者：
Chowdhury AMMA;Katoh H;Hatanaka A;Iwanari H;Nakamura N;Hamakubo T;Natsume T;Waku T;Kobayashi A
越来越多的证据表明转录因子NRF 3（NFE 2L 3）与癌症之间存在生理学关系。在生理条件下，NRF 3被其内质网（ER）隔离抑制。响应于未识别的信号，NRF 3进入细胞核并调节基因表达。然而，NRF 3及其靶基因在癌细胞中核转位的分子机制仍然知之甚少。我们在此报告，NRF 3活性的多重调节控制细胞增殖。我们的分析表明，在生理条件下，NRF 3是迅速降解的ER相关降解（ERAD）泛素连接酶HRD 1和valosin-containing蛋白（VCP）在细胞质中。此外，NRF 3也被β-TRCP降解，β-TRCP是细胞核中Skp 1-Cul 1-F-box蛋白（SCF）泛素连接酶的接头。NRF 3从ER的核转位需要天冬氨酸蛋白酶DNA损伤诱导1同源物2（DDI 2），但不需要抑制其HRD 1-VCP介导的降解。最后，NRF 3介导细胞周期调节因子U2 AF同源基序激酶1（UHMK 1）的基因表达，用于细胞增殖。总的来说，我们的研究为我们提供了许多关于NRF 3在癌细胞中的分子调控和生物学功能的见解。
Accumulated evidence suggests a physiological relationship between the transcription factor NRF3 (NFE2L3) and cancers. Under physiological conditions, NRF3 is repressed by its endoplasmic reticulum (ER) sequestration. In response to unidentified signals, NRF3 enters the nucleus and modulates gene expression. However, molecular mechanisms underlying the nuclear translocation of NRF3 and its target gene in cancer cells remain poorly understood. We herein report that multiple regulation of NRF3 activities controls cell proliferation. Our analyses reveal that under physiological conditions, NRF3 is rapidly degraded by the ER-associated degradation (ERAD) ubiquitin ligase HRD1 and valosin-containing protein (VCP) in the cytoplasm. Furthermore, NRF3 is also degraded by β-TRCP, an adaptor for the Skp1-Cul1-F-box protein (SCF) ubiquitin ligase in the nucleus. The nuclear translocation of NRF3 from the ER requires the aspartic protease DNA-damage inducible 1 homolog 2 (DDI2) but does not require inhibition of its HRD1-VCP-mediated degradation. Finally, NRF3 mediates gene expression of the cell cycle regulator U2AF homology motif kinase 1 (UHMK1) for cell proliferation. Collectively, our study provides us many insights into the molecular regulation and biological function of NRF3 in cancer cells.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.3
作者：
Derjuga, A;Gourley, TS;Blank, V
通讯作者：
Blank, V
影响因子：
5.3
作者：
Kobayashi, A;Kang, MI;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
3.3
作者：
Bordallo, J;Plemper, RK;Wolf, DH
通讯作者：
Wolf, DH
影响因子：
2.7
作者：
Nakamura, Satoki;Okinaka, Keiji;Ohnishi, Kazunori
通讯作者：
Ohnishi, Kazunori