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NRF2 addiction in cancer cells

Hiroshi Kitamura, Hozumi Motohashi
2018 Cancer Science  
O R C I D Hozumi Motohashi http://orcid.org/0000-0002-7261-1033 mutation requires combining Keap1 mutation with additional oncogenic mutations, such as activating mutations of KRAS/HRAS and loss-of-function  ...  Many clinical studies have indeed shown strong correlations between NRF2 activation in tumor tissues and poor clinical outcomes of patients KITAMURA AND MOTOHASHI | 901 suggesting that appropriate  ... 
doi:10.1111/cas.13537 pmid:29450944 pmcid:PMC5891176 fatcat:gtt3xq3znjhejdjmp5xli26qam

The KEAP1-NRF2 System in Healthy Aging and Longevity

Daisuke Matsumaru, Hozumi Motohashi
2021 Antioxidants  
Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental
more » ... ors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes.
doi:10.3390/antiox10121929 pmid:34943032 pmcid:PMC8750203 fatcat:qn7frkzvsraxfifu4qkvzsv6mu

Carcinogenesis and transcriptional regulation through Maf recognition elements

Hozumi Motohashi, Masayuki Yamamoto
2007 Cancer Science  
Motohashi and Yamamoto Maher JM, Cheng X, Slitt AL, Dieter MZ, Klaassen CD.  ...  Motohashi H, O’Connor T, Katsuoka F, Engel JD, Yamamoto M. Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors.  ... 
doi:10.1111/j.1349-7006.2006.00358.x pmid:17129360 fatcat:i546h3l42ffu3pygms6soeixga

Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer

Hiroki Sekine, Hozumi Motohashi
2021 Cancers  
Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap'n'collar) family transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to cancer malignancy by promoting aggressive tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased antioxidant capacity
more » ... underlie the malignant behaviors of NRF2-activated cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of cancers. Since NRF1 maintains proteasome activity by inducing proteasome subunit genes in response to proteasome inhibitors, NRF1 protects cancer cells from proteotoxicity induced by anticancer proteasome inhibitors. An important metabolite that activates NRF1 is UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), which is abundantly generated in many cancer cells from glucose and glutamine via the hexosamine pathway. Thus, the metabolic signatures of cancer cells are closely related to the oncogenic and tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite UDP-GlcNAc.
doi:10.3390/cancers13030541 pmid:33535386 fatcat:kprzuuyi7bfqdo7klsdv3mx3oe

Metabolic features of cancer cells in NRF2 addiction status

Keito Okazaki, Thales Papagiannakopoulos, Hozumi Motohashi
2020 Biophysical Reviews  
These cancer cells are highly dependent on NRF2 activity for their survival and proliferation, a state termed NRF2 addiction (Kitamura et al. 2017; Kitamura and Motohashi 2018) .  ... 
doi:10.1007/s12551-020-00659-8 pmid:32112372 fatcat:izc4z6cqy5gl7m2vy6dgyhewhe

Roles of Nrf2 in cell proliferation and differentiation

Shohei Murakami, Hozumi Motohashi
2015 Free Radical Biology & Medicine  
The KEAP1-NRF2 system plays pivotal roles in defense mechanisms by regulating cellular redox homeostasis. NRF2 is an inducible transcription factor that activates a battery of genes encoding antioxidant proteins and phase II enzymes in response to oxidative stress and electrophilic xenobiotics. The activity of NRF2 is regulated by KEAP1, which promotes the ubiquitination and subsequent degradation of NRF2 under normal conditions and releases the inhibited NRF2 activity upon exposure to the
more » ... ses. Though an impressive contribution of the KEAP1-NRF2 system to the protection from exogenous and endogenous electrophilic insults has been well established, a line of evidence has suggested that the KEAP1-NRF2 system has various novel functions, particularly in cell proliferation and differentiation. Because the proliferation and differentiation of diverse cell types are often influenced and modulated by the cellular redox balance, NRF2 has been considered to control these cellular processes by regulating the cellular levels of reactive oxygen species (ROS). In addition, analyses of the genome-wide distribution of NRF2 have identified new sets of NRF2 target genes whose products are involved in cell proliferation and differentiation but not necessarily in the regulation of oxidative stress. Considering the most characteristic features of NRF2 as an inducible transcription factor, a newly emerged concept proposes that the KEAP1-NRF2 system translates environmental stresses into regulatory network signals in cell fate determination. In this review, we introduce the contribution of NRF2 to lineage-specific differentiation, maintenance and differentiation of stem cells, and proliferation of normal and cancer cells, and we discuss how the response to fluctuating environments modulates cell behavior through the KEAP1-NRF2 system. MURAKAMI et al. 3
doi:10.1016/j.freeradbiomed.2015.06.030 pmid:26119783 fatcat:auq2wcejbrgnribz5rvl3fzpl4

The Keap1–Nrf2 system in cancers: stress response and anabolic metabolism

Yoichiro Mitsuishi, Hozumi Motohashi, Masayuki Yamamoto
2012 Frontiers in Oncology  
Motohashi); and a research grant from the Princess Takamatsu Cancer Research Fund 09-24118 (to Hozumi Motohashi).  ...  ACKNOWLEDGMENTS This work was supported through funding from Grants-in-Aid for Creative Scientific Research (to Masayuki Yamamoto) and Scientific Research (to Masayuki Yamamoto and Hozumi Motohashi)  ... 
doi:10.3389/fonc.2012.00200 pmid:23272301 pmcid:PMC3530133 fatcat:4xdvgwbflvfjxebff4ezrwuriu

Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides

Tomohiro Sawa, Hozumi Motohashi, Hideshi Ihara, Takaaki Akaike
2020 Biomolecules  
Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSSnH, n > 1) are cysteine derivatives that have sulfane sulfur atoms bound to cysteine thiol. Advances in analytical methods that detect and quantify persulfides and polysulfides have shown that CysSSH and related species such as glutathione persulfide occur physiologically and are prevalent in prokaryotes, eukaryotes, and mammals in vivo. The chemical properties and abundance of these compounds suggest a central role for reactive
more » ... fides in cell-regulatory processes. CysSSH and related species have been suggested to act as powerful antioxidants and cellular protectants and may serve as redox signaling intermediates. It was recently shown that cysteinyl-tRNA synthetase (CARS) is a new cysteine persulfide synthase. In addition, we discovered that CARS is involved in protein polysulfidation that is coupled with translation. Mitochondrial activity in biogenesis and bioenergetics is supported and upregulated by CysSSH derived from mitochondrial CARS. In this review article, we discuss the mechanisms of the biosynthesis of CysSSH and related persulfide species, with a particular focus on the roles of CARS. We also review the antioxidative and anti-inflammatory actions of persulfides.
doi:10.3390/biom10091245 pmid:32867265 fatcat:obq7ariasvcjtiotpxltw6v6pi

Characterization of the MurinemafFGene

Ko Onodera, Jordan A. Shavit, Hozumi Motohashi, Fumiki Katsuoka, Jun-etsu Akasaka, James Douglas Engel, Masayuki Yamamoto
1999 Journal of Biological Chemistry  
Motohashi, F. Katsuoka, J. Akasaka, J. D. Engel, and M. Yamamoto, our unpublished observations.  ... 
doi:10.1074/jbc.274.30.21162 pmid:10409670 fatcat:i7soe2hdejg63pyo6nvarqewxe

Nrf2 Transcriptionally Activates themafGGene through an Antioxidant Response Element

Fumiki Katsuoka, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto
2004 Journal of Biological Chemistry  
Motohashi, J. D. Engel, and M. Yamamoto, unpublished observations. 3 F. Katsuoka, H. Motohashi, J. D. Engel, and M. Yamamoto, submitted for publication.  ... 
doi:10.1074/jbc.m411451200 pmid:15574414 fatcat:wb3sopiv6bezvokbzlkpoexd24

NRF2 Pathway Activation by KEAP1 Inhibition Attenuates the Manifestation of Aging Phenotypes in Salivary Glands

Sisca Meida Wati, Daisuke Matsumaru, Hozumi Motohashi
2020 Redox Biology  
Motohashi, H. & Yamamoto, M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol. Med. 10, 549-557 (2004). 20. Blake, D. J. et al.  ...  . & Motohashi, H. The KEAP1-NRF2 system: A thiolbased sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev. 98, 1169-1203 (2018). 34. Yagishita, Y., Uruno, A., Chartoumpekis, D.  ... 
doi:10.1016/j.redox.2020.101603 pmid:32590331 pmcid:PMC7322188 fatcat:e6xoek6e45fkzfyc4rnjkodgrq

Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding [article]

Hideaki Kamata, Mayu Kanamoto, Yoshihiro Tsuchiya, Yuki Nakao, Takafumi Suzuki, Hozumi Motohashi, Masayuki Yamamoto
2018 bioRxiv   pre-print
IKKβ, an essential kinase of NF-κB signaling, is composed of an N-terminal kinase domain (KD) and a C-terminal scaffolding domain, containing a ubiquitin-like domain (ULD). The Hsp90 chaperon has special responsibility for folding of protein kinases including IKKβ. Here, we found that Hsp90 inhibition induced IKKβ degradation, which is partially mediated by Keap1. Geldanamycin (GA), a Hsp90 inhibitor, enhances association of IKKβ with Keap1 through the binding site in KD, and translocates IKKβ
more » ... o detergent-insoluble fractions leading its autophagic degradation. An electrophile tBHQ suppressed Keap1-mediated proteasomal Nrf2 degradation but not autophagic IKKβ degradation. Substitution mutation of Leu353 to Ala in the ULD destabilizes IKKβ, enhances its association with Keap1, translocates it to detergent-insoluble fractions, and causes its autophagic degradation. These results suggest that Keap1 is involved in the degradation of structural destabilized IKKβ and negative regulation of NF-κB under proteotoxic stress.
doi:10.1101/407429 fatcat:ocniihhbbvg5rhrxvjyfyva66u

Nrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers

Keiko Taguchi, Ikuo Hirano, Tohru Itoh, Minoru Tanaka, Atsushi Miyajima, Akira Suzuki, Hozumi Motohashi, Masayuki Yamamoto
2013 Molecular and Cellular Biology  
Keap1-Nrf2 system plays a central role in the stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 activity is abrogated in response to oxidative or electrophilic stresses, leading to Nrf2 stabilization and coordinated activation of cytoprotective genes. We recently found that nuclear accumulation of Nrf2 is significantly increased by simultaneous deletion of Pten and Keap1, resulting in the stronger activation of Nrf2 target genes. To clarify
more » ... he impact of the cross talk between the Keap1-Nrf2 and Pten–phosphatidylinositide 3-kinase–Akt pathways on the liver pathophysiology, in this study we have conducted closer analysis of liver-specificPten::Keap1double-mutant mice (Pten::Keap1-Alb mice). The Pten::Keap1-Alb mice were lethal by 1 month after birth and displayed severe hepatomegaly with abnormal expansion of ductal structures comprising cholangiocytes in a Nrf2-dependent manner. Long-term observation of Pten::Keap1-Alb::Nrf2+/−mice revealed that the Nrf2-heterozygous mice survived beyond 1 month but developed polycystic liver fibrosis by 6 months. Gsk3 directing the Keap1-independent degradation of Nrf2 was heavily phosphorylated and consequently inactivated by the double deletion ofPtenandKeap1genes. Thus, liver-specific disruption ofKeap1andPtenaugments Nrf2 activity through inactivation of Keap1-dependent and -independent degradation of Nrf2 and establishes the Nrf2-dependent molecular network promoting the hepatomegaly and cholangiocyte expansion.
doi:10.1128/mcb.01384-13 pmid:24379438 pmcid:PMC4023823 fatcat:b5vk2xkxc5hxvj33k4ig44udfu

Redox signaling regulated by electrophiles and reactive sulfur species

Motohiro Nishida, Yoshito Kumagai, Hideshi Ihara, Shigemoto Fujii, Hozumi Motohashi, Takaaki Akaike
2016 Journal of clinical biochemistry and nutrition  
Redox signaling is a key modulator of oxidative stress induced by nonspecific insults of biological molecules generated by reactive oxygen species. Current redox biology is revisiting the traditional concept of oxidative stress, such that toxic effects of reactive oxy gen species are protected by diverse antioxidant systems upregu lated by oxidative stress responses that are physiologically mediated by redox dependent cell signaling pathways. Redox signaling is thus precisely regulated by
more » ... nous electrophilic substances that are generated from reactive oxygen species and nitric oxide and its derivative reactive species during stress responses. Among electrophiles formed endogenously, 8 nitro guanosine 3',5' cyclic monophosphate (8 nitro cGMP) has unique cell signaling functions, and pathways for its biosynthesis, signal ing mechanism, and metabolism in cells have been clarified. Reac tive sulfur species such as cysteine hydropersulfides that are abundant in cells are likely involved in 8 nitro cGMP metabolism. These new aspects of redox biology may stimulate innovative and multidisciplinary research in cell and stem cell biology; infectious diseases, cancer, metabolic syndrome, ageing, and neurodegenera tive diseases; and other oxidative stress related disorders. This review focuses on the most recent progress in the biosynthesis, cell signaling, and metabolism of 8 nitro cGMP, which is a likely target for drug development and lead to discovery of novel thera peutics for many diseases.
doi:10.3164/jcbn.15-111 pmid:27013774 pmcid:PMC4788399 fatcat:ee453cc4m5cqzdqqu6ndauldc4

Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming

Yoichiro Mitsuishi, Keiko Taguchi, Yukie Kawatani, Tatsuhiro Shibata, Toshihiro Nukiwa, Hiroyuki Aburatani, Masayuki Yamamoto, Hozumi Motohashi
2012 Cancer Cell  
., 1997; Uruno and Motohashi, 2011) . Under normal conditions, Nrf2 is constantly ubiquitinated by Keap1 and degraded by the proteasome. Exposure to the stimuli inactivates Keap1 and stabilizes Nrf2.  ... 
doi:10.1016/j.ccr.2012.05.016 pmid:22789539 fatcat:gc4i75lhxfdk7hffl6a2oueahm
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