scholarly journals NRF2, a Transcription Factor for Stress Response and Beyond

2020 ◽  
Vol 21 (13) ◽  
pp. 4777 ◽  
Author(s):  
Feng He ◽  
Xiaoli Ru ◽  
Tao Wen
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Regulatory Network ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Genetic Manipulations ◽  
Cellular Processes ◽  
Expression Of Genes ◽  
Nrf2 Activation ◽  
Complex Regulatory Network

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.

scholarly journals Regulation of Wound Healing by the NRF2 Transcription Factor—More Than Cytoprotection

2019 ◽  
Vol 20 (16) ◽  
pp. 3856 ◽  
Author(s):  
Paul Hiebert ◽  
Sabine Werner
Keyword(s):  
Wound Healing ◽  
Transcription Factor ◽  
Chronic Wounds ◽  
Antioxidant Properties ◽  
Cellular Stress Response ◽  
Related Factor ◽  
Loss Of Function ◽  
Nrf2 Activation ◽  
Nrf2 Transcription Factor ◽  
Made In

The nuclear factor-erythroid 2-related factor 2 (NRF2) transcription factor plays a central role in mediating the cellular stress response. Due to their antioxidant properties, compounds activating NRF2 have received much attention as potential medications for disease prevention, or even for therapy. Accumulating evidence suggests that activation of the NRF2 pathway also has a major impact on wound healing and may be beneficial in the treatment of chronic wounds, which remain a considerable health and economic burden. While NRF2 activation indeed shows promise, important considerations need to be made in light of corresponding evidence that also points towards pro-tumorigenic effects of NRF2. In this review, we discuss the evidence to date, highlighting recent advances using gain- and loss-of-function animal models and how these data fit with observations in humans.

scholarly journals NRF2 as a regulator of cell metabolism and inflammation in cancer

2020 ◽  
Vol 41 (4) ◽  
pp. 405-416 ◽  
Author(s):  
Feng He ◽  
Laura Antonucci ◽  
Michael Karin
Keyword(s):  
Oxidative Stress ◽  
Cancer Risk ◽  
Poor Prognosis ◽  
Cell Metabolism ◽  
Transcriptional Regulator ◽  
Negative Control ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Activation

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.

Neighbourhoods in the yeast regulatory network in different physiological states

2020 ◽  
Author(s):  
Arthur M Lesk ◽  
Arun S Konagurthu
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factor ◽  
Stress Response ◽  
Local Structure ◽  
Regulatory Network ◽  
Diauxic Shift ◽  
Central Node ◽  
Similarities And Differences

Abstract Motivation The gene expression regulatory network in yeast controls the selective implementation of the information contained in the genome sequence. We seek to understand how, in different physiological states, the network reconfigures itself to produce a different proteome. Results This article analyses this reconfiguration, focussing on changes in the local structure of the network. In particular, we define, extract and compare the 1-neighbourhoods of each transcription factor, where a 1-neighbourhood of a node in a network is the minimal subgraph of the network containing all nodes connected to the central node by an edge. We report the similarities and differences in the topologies and connectivities of these neighbourhoods in five physiological states for which data are available: cell cycle, DNA damage, stress response, diauxic shift and sporulation. Based on our analysis, it seems apt to regard the components of the regulatory network as ‘software’, and the responses to changes in state, ‘reprogramming’.

scholarly journals Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Jiangang Zhao ◽  
Xu Lin ◽  
Di Meng ◽  
Liping Zeng ◽  
Runzhou Zhuang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Small Cell Lung ◽  
Antioxidant Genes ◽  
Nrf2 Activation ◽  
Underlying Mechanisms

Nuclear factor erythroid-2–related factor-2 (NFE2L2/Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Both Kelch-like ECH-associated protein 1 (Keap1) mutations and Nrf2 mutations contribute to the activation of Nrf2 in non-small cell lung cancer (NSCLC). Nrf2 activity is associated with poor prognosis in NSCLC. Metabolic reprogramming represents a cancer hallmark. Increasing studies reveal that Nrf2 activation promotes metabolic reprogramming in cancer. In this review, we discuss the underlying mechanisms of Nrf2-mediated metabolic reprogramming and elucidate its role in NSCLC. Inhibition of Nrf2 can alter metabolic processes, thus suppress tumor growth, prevent metastasis, and increase sensitivity to chemotherapy in NSCLC. In conclusion, Nrf2 may serve as a therapeutic target for the treatment of NSCLC.

scholarly journals The SEB-1 Transcription Factor Binds to the STRE Motif inNeurospora crassaand Regulates a Variety of Cellular Processes Including the Stress Response and Reserve Carbohydrate Metabolism

2016 ◽  
Vol 6 (5) ◽  
pp. 1327-1343 ◽  
Author(s):  
Fernanda Zanolli Freitas ◽  
Stela Virgilio ◽  
Fernanda Barbosa Cupertino ◽  
David John Kowbel ◽  
Mariana Fioramonte ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Carbohydrate Metabolism ◽  
Cellular Processes ◽  
Reserve Carbohydrate

scholarly journals Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units

2020 ◽  
Vol 2020 ◽  
pp. 1-48
Author(s):  
Upayan Patra ◽  
Urbi Mukhopadhyay ◽  
Arpita Mukherjee ◽  
Rakesh Sarkar ◽  
Mamta Chawla-Sarkar
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Antioxidant Defense ◽  
Cellular Stress Response ◽  
Erythroid Cell ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Defense System ◽  
Cellular Redox ◽  
Cellular Environment

Eukaryotic cells adopt highly tuned stress response physiology under threats of exogenous stressors including viruses to maintain cellular homeostasis. Not surprisingly, avoidance of cellular stress response pathways is an essential facet of virus-induced obligatory host reprogramming to invoke a cellular environment conducive to viral perpetuation. Adaptive cellular responses to oxidative and electrophilic stress are usually taken care of by an antioxidant defense system, core to which lies the redox-responsive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-driven transcriptional cascade. Deregulation of host redox balance and redox stress-sensitive Nrf2 antioxidant defense have been reported for many viruses. In the current study, we aimed to study the modulation of the Nrf2-based host cellular redox defense system in response to Rotavirus (RV) infection in vitro. Interestingly, we found that Nrf2 protein levels decline sharply with progression of RV infection beyond an initial upsurge. Moreover, Nrf2 decrease as a whole was found to be accompanied by active nuclear vacuity of Nrf2, resulting in lowered expression of stress-responsive Nrf2 target genes heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 1 both in the presence and absence of Nrf2-driven transcriptional inducers. Initial induction of Nrf2 concurred with RV-induced early burst of oxidative stress and therefore was sensitive to treatments with antioxidants. Reduction of Nrf2 levels beyond initial hours, however, was found to be independent of the cellular redox status. Furthermore, increasing the half-life of Nrf2 through inhibition of the Kelch-like erythroid cell-derived protein with CNC homology- (ECH-) associated protein 1/Cullin3-RING Box1-based canonical Nrf2 turnover pathway could not restore Nrf2 levels post RV-SA11 infection. Depletion of the Nrf2/HO-1 axis was subsequently found to be sensitive to proteasome inhibition with concurrent observation of increased K48-linked ubiquitination associated with Nrf2. Together, the present study describes robust downregulation of Nrf2-dependent cellular redox defense beyond initial hours of RV infection, justifying our previous observation of potent antirotaviral implications of Nrf2 agonists.

scholarly journals Characterization of the TyrR Regulon in the Rhizobacterium Enterobacter ludwigii UW5 Reveals Overlap with the CpxR Envelope Stress Response

2020 ◽  
Vol 203 (1) ◽  
Author(s):  
Thomas J. D. Coulson ◽  
René M. Malenfant ◽  
Cheryl L. Patten
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Acid Synthesis ◽  
Plant Interactions ◽  
Amino Acid Synthesis ◽  
Content Type ◽  
E Coli ◽  
Expression Of Genes ◽  
Envelope Stress ◽  
Enterobacter Ludwigii

ABSTRACT The TyrR transcription factor controls the expression of genes for the uptake and biosynthesis of aromatic amino acids in Escherichia coli. In the plant-associated and clinically significant proteobacterium Enterobacter ludwigii UW5, the TyrR orthologue was previously shown to regulate genes that encode enzymes for synthesis of the plant hormone indole-3-acetic acid and for gluconeogenesis, indicating a broader function for the transcription factor. This study aimed to delineate the TyrR regulon of E. ludwigii by comparing the transcriptomes of the wild type and a tyrR deletion strain. In E. ludwigii, TyrR positively or negatively regulates the expression of over 150 genes. TyrR downregulated expression of envelope stress response regulators CpxR and CpxP through interaction with a DNA binding site in the intergenic region between divergently transcribed cpxP and cpxR. Repression of cpxP was alleviated by tyrosine. Methyltransferase gene dmpM, which is possibly involved in antibiotic synthesis, was strongly activated in the presence of tyrosine and phenylalanine by TyrR binding to its promoter region. TyrR also regulated expression of genes for aromatic catabolism and anaerobic respiration. Our findings suggest that the E. ludwigii TyrR regulon has diverged from that of E. coli to include genes for survival in the diverse environments that this bacterium inhabits and illustrate the expansion and plasticity of transcription factor regulons. IMPORTANCE Genome-wide RNA sequencing revealed a broader regulatory role for the TyrR transcription factor in the ecologically versatile bacterium Enterobacter ludwigii beyond that of aromatic amino acid synthesis and transport that constitute the role of the TyrR regulon of E. coli. In E. ludwigii, a plant symbiont and human gut commensal, the TyrR regulon is expanded to include genes that are beneficial for plant interactions and response to stresses. Identification of the genes regulated by TyrR provides insight into the mechanisms by which the bacterium adapts to its environment.

Understanding life and death decisions in human leukaemias

2014 ◽  
Vol 42 (4) ◽  
pp. 747-751
Author(s):  
David J. MacEwan ◽  
Lawrence N. Barrera ◽  
Sujitra Keadsanti ◽  
Stuart A. Rushworth ◽  
Niraj M. Shah ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Apoptotic Cell ◽  
Chemotherapy Resistance ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cellular Processes ◽  
Cell Death Mechanisms ◽  
Factor Α ◽  
Human Leukaemia

Human leukaemia cells have an often unique ability to either undergo apoptotic cell death mechanisms or, at other times, undergo proliferative expansion, sometimes to the same stimulus such as the pluripotent cytokine TNFα (tumour necrosis factor α). This potential for life/death switching helps us to understand the molecular signalling machinery that underlies these cellular processes. Furthermore, looking at the involvement of these switching signalling pathways that may be aberrant in leukaemia informs us of their importance in cancer tumorigenesis and how they may be targeted pharmacologically to treat various types of human leukaemias. Furthermore, these important pathways may play a crucial role in acquired chemotherapy resistance and should be studied further to overcome in the clinic many drug-resistant forms of blood cancers. In the present article, we uncover the relationship that exists in human leukaemia life/death switching between the anti-apoptotic pro-inflammatory transcription factor NF-κB (nuclear factor κB) and the cytoprotective antioxidant-responsive transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2). We also discuss recent findings that reveal a major role for Btk (Bruton's tyrosine kinase) in both lymphocytic and myeloid forms of human leukaemias and lymphomas.

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