Beneficial role of Nrf2 in regulating NADPH generation and consumption.

doi:10.1093/TOXSCI/KFR183

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Beneficial role of Nrf2 in regulating NADPH generation and consumption.

Journal Article•DOI•

Beneficial role of Nrf2 in regulating NADPH generation and consumption.

Kai Connie Wu¹, Julia Yue Cui¹, Curtis D. Klaassen¹•Institutions (1)

University of Kansas¹

01 Oct 2011-Toxicological Sciences (Oxford University Press)-Vol. 123, Iss: 2, pp 590-600

TL;DR: It is suggested that Nrf2 protects against environmental insults by promoting the generation of NADPH, which is preferentially consumed by aiding scavenging of oxidative stress rather than fatty acid synthesis and desaturation.

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About: This article is published in Toxicological Sciences.The article was published on 2011-10-01 and is currently open access. It has received 290 citations till now. The article focuses on the topics: Pentose phosphate pathway & Thioredoxin.

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Journal Article•DOI•

The Nrf2 regulatory network provides an interface between redox and intermediary metabolism

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John D. Hayes¹, Albena T. Dinkova-Kostova¹•Institutions (1)

University of Dundee¹

01 Apr 2014-Trends in Biochemical Sciences

TL;DR: Observations suggest Nrf2 directs metabolic reprogramming during stress, which would enable the factor to orchestrate adaptive responses to diverse forms of stress.

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1,482 citations

Journal Article•DOI•

Transcriptional Regulation by Nrf2

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Claudia Tonelli¹, Iok In Christine Chio¹, David A. Tuveson¹, David A. Tuveson²•Institutions (2)

Cold Spring Harbor Laboratory¹, Lustgarten Foundation²

20 Oct 2017-Antioxidants & Redox Signaling

TL;DR: The different modes of regulation of Nrf2 activity are reviewed and the current knowledge of NRF2-mediated transcriptional control is reviewed to provide insight into mechanisms of disease and instruct new treatment strategies.

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Abstract: Significance: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. Unders...

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1,114 citations

Cites background from "Beneficial role of Nrf2 in regulati..."

...The extent of Nrf2 transactivation depends on the levels of Nrf2 protein, as shown in a gene dose response study analyzing expression changes in livers from Nfe2l2-null, wildtype, Keap1 knockdown and Keap1 knockout mice (184)....
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...xenobiotic metabolism show a graded activation by Nrf2, suggesting that the Nrf2-regulated cytoprotective response can be tuned to the intensity of the stress by varying Nrf2 levels (184)....
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...regulation of the principal NADPH-generating enzymes: glucose-6-phosphate dehydrogenase (G6pd), 6-phosphogluconate dehydrogenase (Pgd), isocitrate dehydrogenase 1 (Idh1), and malic enzyme 1 (Me1), as shown in primary cortical astrocytes (91), lung cancer cells (107), mouse small intestine (164), and mouse liver (184)....
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...To prevent OH formation, in conjunction with Hmox1 upregulation, Nrf2 induces the expression of the genes encoding the components of the ferritin complex: the ferritin light polypeptides (Ftl) and heavy polypeptides (Fth) (23, 184)....
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Journal Article•DOI•

Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming

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Yoichiro Mitsuishi¹, Keiko Taguchi¹, Yukie Kawatani¹, Tatsuhiro Shibata, Toshihiro Nukiwa¹, Hiroyuki Aburatani², Masayuki Yamamoto¹, Hozumi Motohashi¹ - Show less +4 more•Institutions (2)

Tohoku University¹, University of Tokyo²

10 Jul 2012-Cancer Cell

TL;DR: It is shown that Nrf2 redirects glucose and glutamine into anabolic pathways, especially under the sustained activation of PI3K-Akt signaling, which enables NRF2 to promote metabolic activities that support cell proliferation in addition to enhancing cytoprotection.

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1,088 citations

Cites background from "Beneficial role of Nrf2 in regulati..."

...While a previous study focused on a cytoprotective aspect of the PPP by analyzing the NADPH production as reducing equivalents for the ROS elimination (Wu et al., 2011), this study showed that the increase of the PPP activity accounts for the Nrf2-dependent proliferation....
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Journal Article•DOI•

NRF2 and the Hallmarks of Cancer.

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Montserrat Rojo de la Vega¹, Eli Chapman¹, Donna D. Zhang¹•Institutions (1)

University of Arizona¹

09 Jul 2018-Cancer Cell

TL;DR: The roles of NRF2 in the hallmarks of cancer are explored, indicating both tumor suppressive and tumor-promoting effects.

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879 citations

Journal Article•DOI•

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

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Antonio Cuadrado¹, Ana I. Rojo¹, Geoffrey Wells², John D. Hayes³, Sharon P. Cousin, William L. Rumsey⁴, Attucks Otis Clinton, Stephen Franklin, Anna-Liisa Levonen⁵, Thomas W. Kensler⁶, Albena T. Dinkova-Kostova³, Albena T. Dinkova-Kostova⁷ - Show less +8 more•Institutions (7)

Spanish National Research Council¹, University College London², University of Dundee³, GlaxoSmithKline⁴, University of Eastern Finland⁵, Fred Hutchinson Cancer Research Center⁶, Johns Hopkins University School of Medicine⁷

01 Apr 2019-Nature Reviews Drug Discovery

TL;DR: An overview of the physiological and pathological roles of NRF2 is provided, emerging pharmacological modulators of theNRF2–KEAP1 axis are presented and associated drug development challenges are highlighted.

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Abstract: The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.

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712 citations

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References

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Journal Article•DOI•

Exploration, normalization, and summaries of high density oligonucleotide array probe level data

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Rafael A. Irizarry¹, Bridget G. Hobbs¹, Francois Collin¹, Yasmin Beazer-Barclay¹, Kristen J. Antonellis¹, Uwe Scherf¹, Terence P. Speed¹ - Show less +3 more•Institutions (1)

Johns Hopkins University¹

01 Apr 2003-Biostatistics

TL;DR: There is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities, and the exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values.

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Abstract: SUMMARY In this paper we report exploratory analyses of high-density oligonucleotide array data from the Affymetrix GeneChip R � system with the objective of improving upon currently used measures of gene expression. Our analyses make use of three data sets: a small experimental study consisting of five MGU74A mouse GeneChip R � arrays, part of the data from an extensive spike-in study conducted by Gene Logic and Wyeth’s Genetics Institute involving 95 HG-U95A human GeneChip R � arrays; and part of a dilution study conducted by Gene Logic involving 75 HG-U95A GeneChip R � arrays. We display some familiar features of the perfect match and mismatch probe ( PM and MM )v alues of these data, and examine the variance–mean relationship with probe-level data from probes believed to be defective, and so delivering noise only. We explain why we need to normalize the arrays to one another using probe level intensities. We then examine the behavior of the PM and MM using spike-in data and assess three commonly used summary measures: Affymetrix’s (i) average difference (AvDiff) and (ii) MAS 5.0 signal, and (iii) the Li and Wong multiplicative model-based expression index (MBEI). The exploratory data analyses of the probe level data motivate a new summary measure that is a robust multiarray average (RMA) of background-adjusted, normalized, and log-transformed PM values. We evaluate the four expression summary measures using the dilution study data, assessing their behavior in terms of bias, variance and (for MBEI and RMA) model fit. Finally, we evaluate the algorithms in terms of their ability to detect known levels of differential expression using the spike-in data. We conclude that there is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities. ∗ To whom correspondence should be addressed

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10,711 citations

Journal Article•DOI•

An nrf2/small maf heterodimer mediates the induction of phase ii detoxifying enzyme genes through antioxidant response elements

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Ken Itoh¹, Tomoki Chiba, Satoru Takahashi¹, Tetsuro Ishii¹, Kazuhiko Igarashi¹, Yasutake Katoh¹, Tatsuya Oyake², Norio Hayashi², Kimihiko Satoh³, Ichiro Hatayama³, Masayuki Yamamoto¹, Yo-ichi Nabeshima - Show less +8 more•Institutions (3)

University of Tsukuba¹, Tohoku University², Hirosaki University³

18 Jul 1997-Biochemical and Biophysical Research Communications

TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.

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3,557 citations

"Beneficial role of Nrf2 in regulati..." refers background in this paper

...Once released from Keap1, Nrf2 translocates into the nucleus, heterodimerizes with a small musculoaponeurotic fibrosarcoma (Maf) protein, and promotes transcription of its target genes (Itoh et al., 1997)....
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Journal Article•DOI•

Bilirubin is an antioxidant of possible physiological importance

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Roland Stocker¹, Yorihiro Yamamoto¹, Antony F. McDonagh², Alexander N. Glazer¹, Bruce N. Ames¹ - Show less +1 more•Institutions (2)

University of California, Berkeley¹, University of California, San Francisco²

27 Feb 1987-Science

TL;DR: The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.

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Abstract: Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.

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3,299 citations

"Beneficial role of Nrf2 in regulati..." refers background in this paper

...Bilirubin is another endogenous antioxidant and has been shown to efficiently scavenge peroxyl radicals (Stocker et al., 1987)....
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Journal Article•DOI•

Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2

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Akira Kobayashi¹, Moon Il Kang¹, Hiromi Okawa¹, Makiko Ohtsuji¹, Yukari Zenke², Tomoki Chiba³, Kazuhiko Igarashi², Masayuki Yamamoto¹ - Show less +4 more•Institutions (3)

University of Tsukuba¹, Hiroshima University², Institute of Medical Science³

15 Aug 2004-Molecular and Cellular Biology

TL;DR: It is found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors.

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Abstract: Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.

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1,908 citations

"Beneficial role of Nrf2 in regulati..." refers background in this paper

...With the negative regulatory system of Keap1, Nrf2 protein has a very rapid turnover, with a half-life less than 20 min (Kobayashi et al., 2004), and thus Nrf2 protein is minimally detectable in unstressed conditions....
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Journal Article•DOI•

Curcumin and cancer: An “old-age” disease with an “age-old” solution

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Preetha Anand¹, Chitra Sundaram¹, Sonia Jhurani¹, Ajaikumar B. Kunnumakkara¹, Bharat B. Aggarwal - Show less +1 more•Institutions (1)

University of Texas MD Anderson Cancer Center¹

18 Aug 2008-Cancer Letters

TL;DR: The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets.

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1,014 citations

"Beneficial role of Nrf2 in regulati..." refers background in this paper

...For example, curcumin also activates AP-1, a transcription factor that promotes cell proliferation (Anand et al., 2008); resveratrol also activates SIRT-1 (Baur, 2010); oltipraz activates constitutive androstane receptor (CAR) and induces Cyp2b10 through CAR activation (Merrell et al., 2008); and…...
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