The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase

Sanghvi, Viraj R.; Leibold, Josef; Mina, Marco; Mohan, Prathibha; Berishaj, Marjan; Li, Zhuoning; Miele, Matthew M.; Lailler, Nathalie; Zhao, Chunli; Stanchina, Elisa de; Viale, Agnès; Akkari, Leila; Lowe, Scott W.; Ciriello, Giovanni; Hendrickson, Ronald C.; Wendel, Hans-Guido

doi:10.1016/j.cell.2019.07.031

Cited by 115 publications

(144 citation statements)

References 73 publications

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“…Extracellular signal-regulated protein kinases (ERK) [24], c-jun N-terminal kinase (JNK) [24], PI3K-AKT [19], protein kinase C (PKC) [25], casein kinase 2 (CK2) [26], and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) [27] were reported to mediate phosphorylation of NRF2 and increase its stability and subsequent transcriptional activity, whereas p38 and GSK3-mediated phosphorylation of NRF2 decreases NRF2 stability [19]. In hepatocellular carcinoma triggered by MYC and KEAP1 inactivation, fructosamine-3-kinase (FN3K), a kinase that triggers protein de-glycation, mediates NRF2 de-glycation that stabilizes NRF2 and executes its oncogenic function [28].…”

Section: Regulation Of Nrf2 Protein Stabilitymentioning

confidence: 99%

NRF2, a Transcription Factor for Stress Response and Beyond

Wen

2020

IJMS

853

495

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Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.

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Section: Regulation Of Nrf2 Protein Stabilitymentioning

confidence: 99%

NRF2, a Transcription Factor for Stress Response and Beyond

Wen

2020

IJMS

853

495

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“…Glycation is increasingly seen as a driver of metabolic disease and aging, and it may elicit specific effects by targeting signaling proteins (Chaudhuri et al, 2018;Kold-Christensen and Johannsen, 2020). In this context, glycation of the ryanodine receptor associated with successive Ca 2+ leakage and mitochondrial damage (Ruiz-Meana et al, 2019), reversible inhibitory glycation of nuclear factor erythroid 2-related factor 2 (Nrf2) (Sanghvi et al, 2019), and methylglyoxal-induced dimerization of Kelch-like ECH-associated protein 1 (KEAP1) with subsequent activation of the KEAP1/Nrf2 transcriptional program (Bollong et al, 2018) have been reported. The latter may play a role in the upregulation of defense systems, such as GLO1 and the ubiquitin-proteasome system (UPS), and may be involved in the hormetic effect of methylglyoxal (Ravichandran et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

Sanzo

Spengler

Leheis

et al. 2020

Preprint

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Posttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products (AGEs) has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devised a proteomic strategy to identify specific sites of carboxymethyllysine (CML) modification, one of the most abundant AGEs. We identified over 1000 sites of CML modification in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we found that protein glycation triggers a proteotoxic response and directly affects the protein degradation machinery. We show that glyoxal induces cell cycle perturbation in primary endothelial cells and that CML modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of AGE modification for cellular function and pinpoint specific protein networks that might become compromised during aging.

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“…Glycation is reversible, which is mediated by Fructosamine-3-kinase (FN3K). Sanghvi et al found that glycation of NRF2 decreased both protein stability and small musculoaponeurotic fibrosarcoma (MAF) protein binding, thereby reducing NRF2 transcriptional output [ 110 ]. This study suggests that NRF2 responds to sugar availability and that targeting FN3K may be a potential therapeutic strategy for NRF2 active cancers.…”

Section: Metabolic Pathways That Stabilize Nrf2mentioning

confidence: 99%

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

DeBlasi

DeNicola

2020

Cancers

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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

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The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase

Abstract: Fructosamine-3-kinase promotes hepatocellular carcinoma by mediating deglycation of NRF2, a protein modification process previously understudied for cellular proteins.

Cited by 115 publications

References 73 publications

NRF2, a Transcription Factor for Stress Response and Beyond

NRF2, a Transcription Factor for Stress Response and Beyond

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

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