Downregulation of UBE2E2 in rat liver cells after hepatocarcinogen treatment facilitates cell proliferation and slowing down of DNA damage response in GST-P-expressing preneoplastic lesions.


:We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P+ foci, compared with GST-P+ foci expressing UBE2E2. However, p21WAF1/CIP1, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA+ cells and γH2AX+ cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P+ foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P+ foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90days. Hepatocarcinogen treatment for 28 or 90days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA+ or γH2AX+ cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P+ proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis.


Toxicol Appl Pharmacol


Mizukami S,Watanabe Y,Saegusa Y,Nakajima K,Ito Y,Masubuchi Y,Yoshida T,Shibutani M




Has Abstract


2017-11-01 00:00:00












  • Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation.

    abstract::Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K(+) channel and Ca(2+) channel blocker effects on QT interval. However, there is no report showing that this techni...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Nozaki Y,Honda Y,Tsujimoto S,Watanabe H,Kunimatsu T,Funabashi H

    更新日期:2014-07-01 00:00:00

  • The toxic effects of monosodium glutamate (MSG) - The involvement of nitric oxide, prostanoids and potassium channels in the reactivity of thoracic arteries in MSG-obese rats.

    abstract::We investigated the potential effects of monosodium glutamate (MSG)-induced obesity with regards to nitric oxide and prostanoid production, as well as potassium channel function, in rat thoracic arteries. Newborn male Wistar rats were injected intraperitoneally with typically reported MSG (4.0 mg/g) once daily for 4 c...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Majewski M,Jurgoński A,Fotschki B,Juśkiewicz J

    更新日期:2018-11-15 00:00:00

  • Protective effects of dithiothreitol on cadmium-induced injury in isolated rat hepatocytes.

    abstract::The biochemical mechanism involved in cadmium-induced cellular injury remains to be elucidated. Various theories have been proposed to account for this action, one of which is an interaction with reduced sulfhydryl (SH) groups of membranes. The ability of a known SH group reducing agent, dithiothreitol (DTT), to inter...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Stacey NH

    更新日期:1986-02-01 00:00:00

  • Tumor necrosis factor involvement in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated endotoxin hypersensitivity in C57BL/6J mice congenic at the Ah locus.

    abstract::An experimental model of endotoxin-induced release of tumor necrosis factor-alpha (TNF) into the serum of C57BL/6J mice congenic at the Ah locus was used to investigate the effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on TNF production. TCDD exposure of Ah-responsive mice (Ahbb) resulted in a dose-dependent i...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Clark GC,Taylor MJ,Tritscher AM,Lucier GW

    更新日期:1991-12-01 00:00:00

  • The surface charge of visible particulate matter predicts biological activation in human bronchial epithelial cells.

    abstract::The physicochemical complexity of airborne particulate matter (PM) has hampered identifying a specific mechanism(s) for its toxicity. In this study, selected physicochemical characteristics (i.e., size, particle number, acidity, and surface charge) were measured on various field PM, derived from urban ambient (St. Lou...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Veronesi B,de Haar C,Lee L,Oortgiesen M

    更新日期:2002-02-01 00:00:00

  • Role of surfactant protein-A (SP-A) in lung injury in response to acute ozone exposure of SP-A deficient mice.

    abstract::Millions are exposed to ozone levels above recommended limits, impairing lung function, causing epithelial damage and inflammation, and predisposing some individuals to pneumonia, asthma, and other lung conditions. Surfactant protein-A (SP-A) plays a role in host defense, the regulation of inflammation, and repair of ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Haque R,Umstead TM,Ponnuru P,Guo X,Hawgood S,Phelps DS,Floros J

    更新日期:2007-04-01 00:00:00

  • Alteration of programmed cell death and gene expression by 5-bromodeoxyuridine during limb development in mice.

    abstract::Some chemicals are known to induce limb malformations in mice. The occurrence of limb abnormality induced by chemical reagents is due to changes in the programmed cell death (PCD). 5-Bromodeoxyuridine (BrdU) is known as a potent teratogen and has been reported to induce polydactyly and other limb malformations in rode...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Nakamura N,Fujioka M,Mori C

    更新日期:2000-09-01 00:00:00

  • Activation of Nrf2 by cadmium and its role in protection against cadmium-induced apoptosis in rat kidney cells.

    abstract::Kidney is the primary target organ in chronic cadmium (Cd) toxicity, and oxidative stress plays an important role in this process. The nuclear transcription factor Nrf2 binds to antioxidant response elements (AREs) and regulates genes involved in protecting cells from oxidative damage. Whether kidney cells respond to ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Chen J,Shaikh ZA

    更新日期:2009-11-15 00:00:00

  • Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice.

    abstract::The mechanism of liver cell injury induced by an overdose of the analgesic acetaminophen (AAP) remains controversial. Recently, it was hypothesized that a significant number of hepatocytes die by apoptosis. Since caspases have been implicated as critical signal and effector proteases in apoptosis, we investigated thei...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Lawson JA,Fisher MA,Simmons CA,Farhood A,Jaeschke H

    更新日期:1999-05-01 00:00:00

  • Percutaneous characterization of the insect repellent DEET and the sunscreen oxybenzone from topical skin application.

    abstract::The synergistic percutaneous enhancement between insect repellent DEET and sunscreen oxybenzone has been proven in our laboratory using a series of in vitro diffusion studies. In this study, we carried out an in vivo study to characterize skin permeation profiles from topical skin application of three commercially ava...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Kasichayanula S,House JD,Wang T,Gu X

    更新日期:2007-09-01 00:00:00

  • Alterations in human B cell calcium homeostasis by polycyclic aromatic hydrocarbons: possible associations with cytochrome P450 metabolism and increased protein tyrosine phosphorylation.

    abstract::Previous studies performed in this laboratory have shown that certain benzo(a)pyrene (BaP) metabolites, such as benzo(a)pyrene-7,8-dihydrodiol (BaP-7,8-diol) and benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), were more effective in elevating intracellular Ca2+ in normal human peripheral blood mononuclear cell (HP...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Mounho BJ,Burchiel SW

    更新日期:1998-03-01 00:00:00

  • Proteomic profiling revealed the functional networks associated with mitotic catastrophe of HepG2 hepatoma cells induced by 6-bromine-5-hydroxy-4-methoxybenzaldehyde.

    abstract::Mitotic catastrophe, a form of cell death resulting from abnormal mitosis, is a cytotoxic death pathway as well as an appealing mechanistic strategy for the development of anti-cancer drugs. In this study, 6-bromine-5-hydroxy-4-methoxybenzaldehyde was demonstrated to induce DNA double-strand break, multipolar spindles...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Zhang B,Huang B,Guan H,Zhang SM,Xu QZ,He XP,Liu XD,Wang Y,Shang ZF,Zhou PK

    更新日期:2011-05-01 00:00:00

  • Inhalation teratology study on monochlorobenzene in rats and rabbits.

    abstract::The embryotoxic and teratogenic potential of inhaled monochlorobenzene (MCB) was evaluated in rats and rabbits. Bred Fischer 344 rats and inseminated New Zealand White rabbits were exposed to 0, 75, 210, or 590 ppm of MCB via inhalation for 6 hr/day during the period of major organogenesis. Exposure to 590 ppm caused ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: John JA,Hayes WC,Hanley TR Jr,Johnson KA,Gushow TS,Rao KS

    更新日期:1984-11-01 00:00:00

  • The hidden effect of estrogenic/antiandrogenic methoxychlor on spermatogenesis.

    abstract::Perinatal and juvenile oral treatment of rats with methoxychlor (MXC) only during development reduces testicular size and Sertoli cell number in those animals as adults. The objectives were to determine if MXC administered orally reduces numbers of spermatogonia and daily sperm production that parallel reduction in Se...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Staub C,Hardy VB,Chapin RE,Harris MW,Johnson L

    更新日期:2002-04-15 00:00:00

  • Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity.

    abstract::Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activation of TAA. Howeve...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Kang JS,Wanibuchi H,Morimura K,Wongpoomchai R,Chusiri Y,Gonzalez FJ,Fukushima S

    更新日期:2008-05-01 00:00:00

  • Role of 3,4-dichlorophenyl methyl sulfone, a metabolite of o-dichlorobenzene, in the changes in hepatic microsomal drug-metabolizing enzymes caused by o-dichlorobenzene administration in rats.

    abstract::2,3- and 3,4-Dichlorophenyl methyl sulfoxides and 2,3- and 3,4-dichlorophenyl methyl sulfones (2,3- and 3,4-DCPSO2Mes) were detected in the urine of rats administered o-dichlorobenzene (o-DCB). After administration of o-DCB to rats, swift decreases were observed in the concentrations of o-DCB in blood, liver, and kidn...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Kato Y,Kimura R

    更新日期:1997-08-01 00:00:00

  • Arsenic inhibits hedgehog signaling during P19 cell differentiation.

    abstract::Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and alt...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Liu JT,Bain LJ

    更新日期:2014-12-15 00:00:00

  • EPAC expression and function in cardiac fibroblasts and myofibroblasts.

    abstract:UNLABELLED:In the heart, cardiac fibroblasts (CF) and cardiac myofibroblasts (CMF) are the main cells responsible for wound healing after cardiac insult. Exchange protein activated by cAMP (EPAC) is a downstream effector of cAMP, and it has been not completely studied on CF. Moreover, in CMF, which are the main cells r...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Olmedo I,Muñoz C,Guzmán N,Catalán M,Vivar R,Ayala P,Humeres C,Aránguiz P,García L,Velarde V,Díaz-Araya G

    更新日期:2013-10-15 00:00:00

  • Mdr1a, Bcrp and Mrp2 regulate the efficacy and toxicity of mesaconitine and hypaconitine by altering their tissue accumulation and in vivo residence.

    abstract::Mesaconitine (MA) and hypaconitine (HA) are the main bioactive/toxic alkaloids of Aconitum carmichaelii Debx, and MDR1, BCRP and MRP2 are involved in their efflux in vitro. This study aimed to explore the effects of Mdr1a, Bcrp and Mrp2 on the efficacy/toxicity of MA and HA by using efflux transporter gene knockout mo...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Li X,Ou X,Luo G,Ou X,Xie Y,Ying M,Qu W,Zuo H,Qi X,Wang Y,Liu Z,Zhu L

    更新日期:2020-12-15 00:00:00

  • Predicting the oral uptake efficiency of chemicals in mammals: combining the hydrophilic and lipophilic range.

    abstract::Environmental risk assessment requires models for estimating the bioaccumulation of untested compounds. So far, bioaccumulation models have focused on lipophilic compounds, and only a few have included hydrophilic compounds. Our aim was to extend an existing bioaccumulation model to estimate the oral uptake efficiency...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: O'Connor IA,Huijbregts MA,Ragas AM,Hendriks AJ

    更新日期:2013-01-01 00:00:00

  • Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice.

    abstract::Arsenic is an environmental toxicant and carcinogen. Exposure to arsenic is associated with development of liver fibrosis and portal hypertension through ill defined mechanisms. We evaluated hepatic fibrogenesis after long term arsenic exposure in a murine model. BALB/c mice were exposed to arsenic by daily gavages of...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Ghatak S,Biswas A,Dhali GK,Chowdhury A,Boyer JL,Santra A

    更新日期:2011-02-15 00:00:00

  • Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: a case study of lindane-induced neurotoxicity.

    abstract::Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Croom EL,Shafer TJ,Evans MV,Mundy WR,Eklund CR,Johnstone AF,Mack CM,Pegram RA

    更新日期:2015-02-15 00:00:00

  • The uptake and elimination of 1,1,1-trichloroethane during and following inhalation exposures in rats.

    abstract::The pharmacokinetics of 1,1,1-trichloroethane (TRI) was studied in male Sprague-Dawley rats in order to characterize and quantify TRI uptake and elimination oby direct measurements of the inhaled and exhaled compound. Fifty or 500 ppm TRI was inhaled for 2 hr through a one-way breathing valve by unanesthetized rats of...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Dallas CE,Ramanathan R,Muralidhara S,Gallo JM,Bruckner JV

    更新日期:1989-05-01 00:00:00

  • Sex-related differences in mouse renal metabolism and toxicity of acetaminophen.

    abstract::The objective of this study is to elucidate the role of cytochrome P450 2E1 in the metabolic activation of acetaminophen (APAP) in mouse kidneys. With the kidney microsomes from C3H/HeJ mice, a significant sex-related difference was observed in the NADPH-dependent formation of a reactive APAP metabolite which was trap...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Hu JJ,Lee MJ,Vapiwala M,Reuhl K,Thomas PE,Yang CS

    更新日期:1993-09-01 00:00:00

  • Gene expression influences on metal immunomodulation.

    abstract::Heavy metals in the environment originate from both human activities and natural processes. Exposure to these metals can result in important changes to immune activity. Depending on the metal and dose, these changes can result in enhanced immune function, diminished immune responses, or altered responses that produce ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章,评审


    authors: Lynes MA,Fontenot AP,Lawrence DA,Rosenspire AJ,Pollard KM

    更新日期:2006-01-01 00:00:00

  • In vitro effects of hydroquinone, benzoquinone, and doxorubicin on mouse and human bone marrow cells at physiological oxygen partial pressure.

    abstract::A comparative study was undertaken in order to assess the hematotoxic effects of hydroquinone (HQ), 1,4-benzoquinone (BQ), and doxorubicin (DX) on mouse and human bone marrow (BM) cells. Initial experiments indicated that the inhibitory effects of near-ambient pO2 and HQ on granulocyte/macrophage colony-stimulating fa...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Colinas RJ,Burkart PT,Lawrence DA

    更新日期:1994-11-01 00:00:00

  • Mitochondria work as reactors in reducing arsenate to arsenite.

    abstract::Arsenate (AsV) is a structural analogue of phosphate (P(i)), yet its toxic effect is likely due to its reduction to the more toxic arsenite (AsIII), the mechanism of which is still unclear. Since mitochondria take up AsV as they do P(i), they may reduce AsV to AsIII. To test this hypothesis isolated rat liver mitochon...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Németi B,Gregus Z

    更新日期:2002-08-01 00:00:00

  • Extension of a PBPK model for ethylene glycol and glycolic acid to include the competitive formation and clearance of metabolites associated with kidney toxicity in rats and humans.

    abstract::A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmaco...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Corley RA,Saghir SA,Bartels MJ,Hansen SC,Creim J,McMartin KE,Snellings WM

    更新日期:2011-02-01 00:00:00

  • Modulation of N-methyl-N'-nitro-nitrosoguanidine multiorgan carcinogenesis by dehydroepiandrosterone in rainbow trout.

    abstract::Dehydroepiandrosterone (DHEA) and its sulfate conjugate are the major circulating steroids in human plasma. Low levels of these adrenal steroids are associated with a number of human diseases including certain cancers. In animal studies, DHEA is chemopreventive toward both spontaneous and chemically induced cancers. A...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Orner GA,Hendricks JD,Arbogast D,Williams DE

    更新日期:1996-12-01 00:00:00

  • P-glycoprotein activation by 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5) in rat distal ileum: ex vivo and in vivo studies.

    abstract::In vitro studies showed that 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5) increases P-glycoprotein (P-gp) expression and activity in Caco-2 cells, preventing xenobiotic toxicity. The present study aimed at investigating TX5 effects on P-gp expression/activity using Wistar Han rats: a) in vivo, evaluating ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Rocha-Pereira C,Ghanem CI,Silva R,Casanova AG,Duarte-Araújo M,Gonçalves-Monteiro S,Sousa E,Bastos ML,Remião F

    更新日期:2020-01-01 00:00:00