scholarly journals Mechanism of activation and regulation of Deubiquitinase activity in MINDY1 and MINDY2

2021 ◽  
Author(s):  
Syed Arif Abdul Rehman ◽  
Lee A. Armstrong ◽  
Sven M. Lange ◽  
Yosua Adi Kristariyanto ◽  
Tobias W. Grawert ◽  
...  
Keyword(s):  
Chain Length ◽  
Catalytic Mechanism ◽  
Catalytic Domain ◽  
Catalytic Triad ◽  
List Type ◽  
Dependent Manner ◽  
Ubiquitin Chain ◽  
Polyubiquitin Chains ◽  
Ubiquitin Binding ◽  
Exquisite Specificity

ABSTRACTOf the eight distinct polyubiquitin chains that can be assembled, K48-linked ubiquitin is the most well-understood linkage and modification of proteins with K48 chains targets the modified protein for degradation. By removing ubiquitin from substrates or trimming ubiquitin chains, deubiquitinases (DUBs) can modulate the outcome of ubiquitylation. MINDY1 and MINDY2 are members of the MINDY family of DUBs that have exquisite specificity for cleaving K48-linked polyubiquitin. Being recently discovered DUBs, we have a poor understanding of their catalytic mechanism. By analysing crystal structures of MINDY1 alone and in complex with monoubiquitin or K48-linked ubiquitin chains, we here reveal how substrate interaction relieves autoinhibition and activates the DUB. Further, our analyses reveal a non-canonical catalytic triad composed of Cys-His-Thr and explain how these DUBs sense both ubiquitin chain length and linkage type to trim K48-linked ubiquitin chains. Our findings highlight the multiple layers of regulation modulating DUB activity in MINDY1 and MINDY2.SynopsisStructure of MINDY1 in complex with K48-linked diUb reveals how K48-linked polyUb is recognized and cleavedThe Cys loop mediates autoinhibition of the DUB and substrate binding at the S1 and S1’ sites relieves autoinhibition and activates the enzyme for catalysisMINDY1 uses a non-canonical catalytic triad composed of Cys-His-ThrMINDY1 has five ubiquitin binding sites within its catalytic domain and switches from exo to endo cleavage in a ubiquitin chain length-dependent manner

Chemokine degradation by the Group A streptococcal serine proteinase ScpC can be reconstituted in vitro and requires two separate domains

2009 ◽  
Vol 422 (3) ◽  
pp. 533-542 ◽  
Author(s):  
Andrea Fritzer ◽  
Birgit Noiges ◽  
Daniela Schweiger ◽  
Angelika Rek ◽  
Andreas J. Kungl ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Serine Proteinase ◽  
Interferon Γ ◽  
Catalytic Triad ◽  
Terminal Region ◽  
Dependent Manner ◽  
Human Pathogens ◽  
Platelet Factor ◽  
Monocyte Chemoattractant Protein 1

Streptococcus pyogenes is one of the most common human pathogens and possesses diverse mechanisms to evade the human immune defence. One example of its immune evasion is the degradation of the chemokine IL (interleukin)-8 by ScpC, a serine proteinase that prevents the recruitment of neutrophils to an infection site. By applying the ANTIGENome technology and using human serum antibodies, we identified Spy0416, annotated as ScpC, as a prominent antigen that induces protective immune responses in animals. We demonstrate here for the first time that the recombinant form of Spy0416 is capable of IL-8 degradation in vitro in a concentration- and time-dependent manner. Mutations in the conserved amino acid residues of the catalytic triad of Spy0416 completely abolished in vitro activity. However, the isolated predicted proteinase domain does not exhibit IL-8-degrading activity, but is dependent on the presence of the C-terminal region of Spy0416. Binding to IL-8 is mainly mediated by the catalytic domain. However, the C-terminal region modulates substrate binding, indicating that the proteolytic activity is amenable to regulation via the non-catalytic regions. The specificity for human substrates is not restricted to IL-8, since we also detected in vitro protease activity for another CXC chemokine GRO-α (growth-related oncogene α), but not for NAP-2 (neutrophil-activating protein 2), SDF (stromal-cell-derived factor)-1α, PF-4 (platelet factor 4), I-TAC (interferon-γ-inducible T-cell α-chemoattractant), IP-10 (interferon-γ-inducible protein 10) and MCP-1 (monocyte chemoattractant protein 1). The degradation of two human CXC chemokines in vitro, the high sequence conservation, the immunogenicity of the protein in humans and the shown protection in animal studies suggest that Spy0416 is a promising vaccine candidate for the prevention of infections by S. pyogenes.

scholarly journals A Mechanism for Protein Monoubiquitination Dependent on a trans-Acting Ubiquitin-binding Domain

2013 ◽  
Vol 288 (23) ◽  
pp. 16206-16211 ◽  
Author(s):  
Antonio Herrador ◽  
Sébastien Léon ◽  
Rosine Haguenauer-Tsapis ◽  
Olivier Vincent
Keyword(s):  
Chain Length ◽  
Ubiquitin Ligase ◽  
Functional Outcomes ◽  
Binding Domain ◽  
Chain Elongation ◽  
Related Protein ◽  
Ubiquitin Chain ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

The length of the ubiquitin chain on a substrate dictates various functional outcomes, yet little is known about its regulation in vivo. The yeast arrestin-related protein Rim8/Art9 is monoubiquitinated in vivo by the Rsp5 ubiquitin ligase. This also requires Vps23, a protein that displays an ubiquitin-E2 variant (UEV) domain. Here, we report that binding of the UEV domain to Rim8 interferes with ubiquitin chain elongation and directs Rim8 monoubiquitination. We propose that Vps23 UEV competes with Rsp5 HECT N-lobe for binding to the first conjugated ubiquitin, thereby preventing polyubiquitination. These findings reveal a novel mechanism to control ubiquitin chain length on substrates in vivo.

Homology modelling and structural analysis of human arylamine N-acetyltransferase NAT1: evidence for the conservation of a cysteine protease catalytic domain and an active-site loop

2001 ◽  
Vol 356 (2) ◽  
pp. 327-334 ◽  
Author(s):  
Fernando RODRIGUES-LIMA ◽  
Claudine DELOMÉNIE ◽  
Geoffrey H. GOODFELLOW ◽  
Denis M. GRANT ◽  
Jean-Marie DUPRET
Keyword(s):  
Crystal Structure ◽  
Cysteine Protease ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Catalytic Domain ◽  
Homology Modelling ◽  
Metabolic Activation ◽  
Cysteine Proteases ◽  
Catalytic Triad ◽  
Quality Model

Arylamine N-acetyltransferases (EC 2.3.1.5) (NATs) catalyse the biotransformation of many primary arylamines, hydrazines and their N-hydroxylated metabolites, thereby playing an important role in both the detoxification and metabolic activation of numerous xenobiotics. The recently published crystal structure of the Salmonella typhimurium NAT (StNAT) revealed the existence of a cysteine protease-like (Cys-His-Asp) catalytic triad. In the present study, a three-dimensional homology model of human NAT1, based upon the crystal structure of StNAT [Sinclair, Sandy, Delgoda, Sim and Noble (2000) Nat. Struct. Biol. 7, 560–564], is demonstrated. Alignment of StNAT and NAT1, together with secondary structure predictions, have defined a consensus region (residues 29–131) in which 37% of the residues are conserved. Homology modelling provided a good quality model of the corresponding region in human NAT1. The location of the catalytic triad was found to be identical in StNAT and NAT1. Comparison of active-site structural elements revealed that a similar length loop is conserved in both species (residues 122–131 in NAT1 model and residues 122–133 in StNAT). This observation may explain the involvement of residues 125, 127 and 129 in human NAT substrate selectivity. Our model, and the fact that cysteine protease inhibitors do not affect the activity of NAT1, suggests that human NATs may have adapted a common catalytic mechanism from cysteine proteases to accommodate it for acetyl-transfer reactions.

Orchestra for assembly and fate of polyubiquitin chains

2005 ◽  
Vol 41 ◽  
pp. 1-14 ◽  
Author(s):  
Kuhlbrodt Kirsten ◽  
Mouysset Julien ◽  
Hoppe Thorsten
Keyword(s):  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Chain Elongation ◽  
Polyubiquitin Chain ◽  
Ubiquitin Chain ◽  
Polyubiquitin Chains ◽  
Intracellular Signals ◽  
Ubiquitin Binding ◽  
Ubiquitin Ligase E3 ◽  
Ubiquitin Conjugating Enzyme

Selective protein degradation by the 26 S proteasome usually requires a polyubiquitin chain attached to the protein substrate by three classes of enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3). This reaction can produce different polyubiquitin chains that, depending on size and linkage type, can provide distinct intracellular signals. Interestingly, polyubiquitination is sometimes regulated by additional conjugation factors, called E4s (polyubiquitin chain conjugation factors). Yeast UFD2 (ubiquitin fusion degradation protein-2), the first E4 to be described, binds to the ubiquitin moieties of preformed conjugates and catalyses ubiquitin-chain elongation together with E1, E2, and E3. Recent studies have illustrated that the E4 enzyme UFD2 co-operates with an orchestra of ubiquitin-binding factors in an escort pathway to transfer and deliver polyubiquitinated substrates to the 26 S proteasome. Here we propose a model in which E4-dependent polyubiquitination pathways are modulated by different ubiquitin-binding proteins, using ataxin-3 as an example.

scholarly journals Structural and mechanistic studies of human chitinase

2014 ◽  
Vol 70 (a1) ◽  
pp. C445-C445
Author(s):  
Firas Fadel ◽  
Yuguang Zhao ◽  
Alexandra Cousido-Siah ◽  
Eduardo Howard ◽  
André Mitschler ◽  
...  
Keyword(s):  
Catalytic Mechanism ◽  
Catalytic Domain ◽  
Catalytic Triad ◽  
Chitin Binding Domain ◽  
X Ray ◽  
Detailed Structural Analysis ◽  
Acidic Mammalian Chitinase ◽  
Hydrogen Network ◽  
First Time

Chitinases are enzymes that hydrolyze chitin, a glucosamine polymer synthesized by lower organisms for structural purposes [1]. While humans do not synthetize chitin, they express two active chitinases, Chitotriosidase (hCHIT1) and Acidic Mammalian Chitinase (hAMCase). Both enzymes attracted attention due to their upregulation in immune system disorders [2,3]. They consist of a catalytic domain of 39 kDa and a chitin binding domain, joined by a hinge. The active site shows a cluster of three conserved acidic residues, E140, D138 and D136, linked by H-bonds, where D138 and E140 are involved in the hydrolysis reaction [1,3]. To increase our knowledge on the catalytic mechanism of human chitinases, we conducted a detailed structural analysis on hCHIT1. For this, we have improved the X-ray resolution of the apo hCHIT1 catalytic domain to 1Å. We investigated the protonation state on the catalytic site and detected a double conformation of D138, one in contact with D136 and a second one in contact with E140. Our analysis revealed for the first time different protonation states for each conformation of D138 (fig1). Interestingly, our X-ray data suggest that the catalytic E140, supposed to donate a proton in the catalytic reaction, is deprotonated in the apo form. To gain insight on the proton transition pathway during the hydrolysis, we have solved the X-ray structure of hCHIT1 complexed with the substrate at 1.05 Å. In comparison with the apo form, this structure shows a rearrangement of the protonation states of the catalytic triad triggered by the binding of the substrate. Our results led us to suggest a new hydrolysis model involving changes in the hydrogen bond network of the catalytic triad accompanied by a flip of D138 towards D136. This contributes to protonate E140, which then donates the proton to the substrate. To confirm the role of the active site's hydrogen network, we are currently studying CHIT1 by neutron crystallography and quantum mechanics.

scholarly journals New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM

2015 ◽  
Vol 71 (7) ◽  
pp. 1455-1470 ◽  
Author(s):  
Firas Fadel ◽  
Yuguang Zhao ◽  
Raul Cachau ◽  
Alexandra Cousido-Siah ◽  
Francesc X. Ruiz ◽  
...  
Keyword(s):  
Catalytic Mechanism ◽  
Catalytic Domain ◽  
Glycosyl Hydrolase ◽  
Catalytic Triad ◽  
X Ray Diffraction ◽  
Protonation State ◽  
Enzymatic Mechanism ◽  
Excess Concentration ◽  
Hydrolase Family

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, anN-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 Å (PDB entry 1waw) to 0.95–1.10 Å for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities.

scholarly journals OTUB1 is a key regulator of RIG-I dependent immune signalling and is targeted for proteasomal degradation by influenza A NS1

2019 ◽  
Author(s):  
Akhee Sabiha Jahan ◽  
Elise Biquand ◽  
Raquel Muñoz-Moreno ◽  
Agathe Le Quang ◽  
Chris Ka-Pun Mok ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Proteasomal Degradation ◽  
List Type ◽  
Dependent Manner ◽  
Mitochondrial Membranes ◽  
Polyubiquitin Chains ◽  
Antiviral Responses ◽  
Wide Range

SummaryDeubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host innate immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, DUBs that regulate this pathway have not been identified. Using a ubiquitin C-terminal electrophile, we profiled DUBs that function during influenza A virus (IAV) infection, and isolated OTUB1 as a key regulator of RIG-I dependent antiviral responses. OTUB1 was interferon-inducible, and interacted with RIG-I, viral PB2 and NS1. Upon infection, OTUB1 relocalised from the nucleus to mitochondrial membranes, and activated the RIG-I signaling complex via hydrolysis of K48 polyubiquitin chains and by forming a repressive complex with UBCH5c. Using a reconstituted system composed of in vitro translated [35S]IRF3, purified RIG-I, mitochondrial membranes and cytosol expressing OTUB1 variants, we recapitulated the mechanism of OTUB1-dependent RIG-I activation. A wide range of IAV NS1 proteins triggered proteasomal degradation of OTUB1, thereby antagonizing the RIG-I signaling cascade and antiviral responses.HighlightsOTUB1 is induced during influenza A virus infections in an IFN-I dependent mannerOTUB1 regulates the RIG-I complex by hydrolysing K48-linked polyubiquitin chains and by sequestering UBCH5c to prevent K48 polyubiquitylationOptimal K63 versus K48 polyubiquitin chain concentrations determine RIG-I activationInfluenza NS1 targets OTUB1 for proteasomal degradation

Rationalizing the pH-Activity Response for Escherichia Coli’s Glycinamide Ribonucleotidetransformylase Through Computational Methods

2019 ◽  
Author(s):  
Adrian Roitberg ◽  
Pancham Lal Gupta
Keyword(s):  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Ph Dependence ◽  
Ph Effects ◽  
Dependent Manner ◽  
E Coli ◽  
Gar Tfase ◽  
Activity Curve ◽  
Ph Dependent ◽  
Formyl Transfer

<div>Human Glycinamide ribonucleotide transformylase (GAR Tfase), a regulatory enzyme in the de novo purine biosynthesis pathway, has been established as an anti-cancer target. GAR Tfase catalyzes the formyl transfer reaction from the folate cofactor to the GAR ligand. In the present work, we study E. coli GAR Tfase, which has high sequence similarity with the human GAR Tfase with most functional residues conserved. E. coli GAR Tfase exhibits structural changes and the binding of ligands that varies with pH which leads to change the rate of the formyl transfer reaction in a pH-dependent manner. Thus, the inclusion of pH becomes essential for the study of its catalytic mechanism. Experimentally, the pH-dependence of the kinetic parameter kcat is measured to evaluate the pH-range of enzymatic activity. However, insufficient information about residues governing the pH-effects on the catalytic activity leads to ambiguous assignments of the general acid and base catalysts and consequently its catalytic mechanism. In the present work, we use pH-replica exchange molecular dynamics (pH-REMD) simulations to study the effects of pH on E. coli GAR Tfase enzyme. We identify the titratable residues governing the pH-dependent conformational changes in the system. Furthermore, we filter out the protonation states which are essential in maintaining the structural integrity, keeping the ligands bound and assisting the catalysis. We reproduce the experimental pH-activity curve by computing the population of key protonation states. Moreover, we provide a detailed description of residues governing the acidic and basic limbs of the pH-activity curve.</div>

184 Two types of anti-TIGIT antibodies with distinct binding epitope and functional activities

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A198-A198
Author(s):  
Tingting Zhong ◽  
Xinghua Pang ◽  
Zhaoliang Huang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Mixed Culture ◽  
Cell Activity ◽  
Cross Reactivity ◽  
Binding Activity ◽  
Jurkat Cells ◽  
List Type ◽  
Dependent Manner ◽  
Vitro Assay

BackgroundTIGIT is an inhibitory receptor mainly expressed on natural killer (NK) cells, CD8+ T cells, CD4+ T cells and Treg cells. TIGIT competes with CD226 for binding with CD155. In cancers, CD155 has been reported to up-regulate on tumor cells, and TIGIT was found to increase on TILs.1 Activation of TIGIT/CD155 pathway would mediate immunosuppression in tumor; while blockade of TIGIT promotes anti-tumor immune response.MethodsAK126 and AK113 are two humanized anti-human TIGIT monoclonal antibodies developed by Akesobio. Binding activity of AK126 and AK113 to human TIGIT, and competitive binding activity with CD155 and CD112, were performed by using ELISA, Fortebio, and FACS assays. Cross-reactivity with cynomolgus monkey TIGIT and epitope binning were also tested by ELISA assay. In-vitro assay to investigate the activity to promote IL-2 secretion was performed in mixed-culture of Jurkat-TIGIT cells and THP-1 cells.ResultsAK126 and AK113 could specifically bind to human TIGIT with comparative affinity and effectively blocked the binding of human CD155 and CD112 to human TIGIT. X-ray crystal structure of TIGIT and PVR revealed the C’-C’’ loop and FG loop regions of TIGIT are the main PVR interaction regions.2 The only amino acid residue differences in these regions between human and monkey TIGIT are 70C and 73D. AK126 binds to both human and monkey TIGIT, AK113 binds only to monkey TIGIT. This suggests that these residues are required for AK113 binding to human TIGIT, but not required for AK126. Interestingly, results from cell-based assays indicated that AK126 and AK113 showed significantly different activity to induce IL-2 secretion in mixed-culture of Jurkat-TIGIT cells and THP-1 cells (figure 1A and B), in which AK126 had a comparable capacity of activity to 22G2, a leading TIGIT mAb developed by another company, to induce IL-2 secretion, while, AK113 showed a significantly higher capacity than 22G2 and AK126.Abstract 184 Figure 1Anti-TIGIT Antibodies Rescues IL-2 Production in Vitro T-Cell Activity Assay in a dose dependent manner. Jurkat-TIGIT cells (Jurkat cells engineered to over-express human TIGIT) were co-cultured with THP-1 cells, and stimulated with plate-bound anti-CD3 mAb in the presence of TIGIT ligand CD155 (A) or CD112 (B) with anti-TIGIT antibodies. After incubated for 48h at 37° C and 5.0% CO2, IL-2 levels were assessed in culture supernatants by ELISA. Data shown as mean with SEM for n = 2.ConclusionsWe discovered two distinct types of TIGIT antibodies with differences in both epitope binding and functional activity. The mechanism of action and clinical significance of these antibodies require further investigation.ReferencesSolomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 2018;67:1659–1667.Stengel KF, Harden-Bowles K, Yu X, et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci USA 2012;109:5399–5404.

734 A novel NQO1 specific anti-tumor agent, SBSC-S3001, selectively regresses the growth of tumors with high NQO1 expression

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A778-A778
Author(s):  
Minhyuk Yun ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Changhoon In ◽  
Gyu-Young Moon ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
High Expression ◽  
List Type ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Quinone Oxidoreductase ◽  
Key Enzymes

BackgroundNAD(P)H-quinone oxidoreductase 1 (NQO1) is a cytosolic two-electron oxidoreductase overexpressed in many types of cancers, including breast cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, uterine cervical cancer, melanoma, and lung cancer.1Up-regulation of NQO1 protects cells from oxidative stress and various cytotoxic quinones and is associated with late clinical stage, poor prognosis and lymph node metastasis.2 3 NQO1 increases stability of HIF-1α protein, which has been implicated in survival, proliferation, and malignance of cancer.1 Therefore, accumulating evidences suggest NQO1 as a promising therapeutic target for cancer. Accordingly, we have characterized the effect of a novel synthetic NQO1 substrate SBSC-S3001, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1.MethodsIn vitro cytotoxicity was determined by sulforhodamine B (SRB) assay in cancer cells with high NQO1 expression and CRISPR-mediated NQO1 knockout cells. The effect of SBSC-S3001 on the energy metabolism pathway was evaluated by western blot analysis of metabolism associated proteins from NQO1-overexpressed cancer cells treated with the compound for 24 hours. In vivo anti-tumor activity was evaluated in MC38 syngeneic and DLD-1 orthotopic mice models.ResultsSBSC-S3001 exhibited selective cytotoxicity in cancer cells with high expression of NQO1 in a dose-dependent manner. The cytotoxicity was observed in both normoxia and hypoxia conditions, correlating with the energy metabolism, mitochondrial biogenesis, and cancer proliferative pathways. Also, stronger cytotoxicity was observed in NQO1-overexpressed cancer cells treated with SBSC-S3001 compared to beta-lapachone and analogue treatment.4 When evaluated in vivo, SBSC-S3001 effectively inhibited the growth of syngeneic and orthotopic tumors when administered as a monotherapy. SBSC-S3001 treatment associated with reduction in key enzymes of the glycolytic pathway (LDHa and GAPDH) and HIF-1α and increase in levels of mitochondrial oxidative phosphorylation (OXPHOS) complex.ConclusionsTreatment of SBSC-S3001, a novel, NQO1-specific substrate reduces HIF-1α and key enzymes associated with glycolysis and suppresses the growth of tumors overexpressing NQO1. Further characterization of SBSC-S3001 as a novel metabolic anti-cancer agent for cancers with NQO1 overexpression is warranted.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2031.ReferencesOh ET, Kim JW, Kim JMet. al., NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 2016; 14:13593.Ma, Y. et al. NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 2014;14: 414Yang, Y. et al. Clinical implications of high NQO1 expression in breast cancers. J. Exp. Clin. Cancer Res 2014;33:144.Yang Y, Zhou X, Xu M, et al., β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 2017;7:2681.

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