Journal Article

Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation

Iwanari, Hiroko, Kobayashi, Akira, Katoh, Hiroki, Hamakubo, Takao, Waku, Tsuyoshi, Chowdhury, A. M. Masudul Azad, Nakamura, Nanami, Natsume, Tohru, Hatanaka, Atsushi

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/31 / 38/109 / 38/61 / 38/89 / 42 / 631/337/474/582 / 631/337/572/2102 / 64 / 82 / 82/58 / 82/80 / Animals / Aspartic Acid Proteases - genetics / Aspartic Acid Proteases - metabolism / Aspartic endopeptidase / Basic-Leucine Zipper Transcription Factors - genetics / Basic-Leucine Zipper Transcription Factors - metabolism / beta-Transducin Repeat-Containing Proteins - genetics / beta-Transducin Repeat-Containing Proteins - metabolism / Cancer / Cell cycle / Cell Cycle - genetics / Cell growth / Cell Line, Tumor / Cell Nucleus - metabolism / Cell Proliferation / Cercopithecus aethiops / COS Cells / Cullin Proteins - genetics / Cullin Proteins - metabolism / Cytoplasm / Cytosol - metabolism / DNA damage / Endoplasmic reticulum / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum-Associated Degradation / Epithelial Cells - metabolism / Epithelial Cells - pathology / F-box protein / Gene expression / Gene Expression Regulation, Neoplastic / HCT116 Cells / HeLa Cells / Homology / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Molecular modelling / multidisciplinary / Nuclear transport / Physiology / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / S-Phase Kinase-Associated Proteins - genetics / S-Phase Kinase-Associated Proteins - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Stem Cell Factor - genetics / Stem Cell Factor - metabolism / Translocation / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Valosin Containing Protein - genetics / Valosin Containing Protein - metabolism / Valosin-containing protein