Activation of ERK and JNK signaling pathways by mycotoxin citrinin in human cells

Chang, Chia-Hao; Yu, Feng‐Yih; Wang, Liting; Lin, Yi-Shen; Liu, Biing-Hui

doi:10.1016/j.taap.2009.03.021

Cited by 40 publications

(22 citation statements)

References 43 publications

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“…Activation of the ERK and JNK pathways resulting in increased protein levels of Egr‐1, Elk‐1, c‐Fos, and/or c‐Jun were documented in some chemically treated cells. ( 26,27,29 ) Also, the apoptotic effect was accompanied by increased transcription activity of Egr‐1 and/or AP‐1 which are downstream effectors of the ERK and JNK pathways.…”

Section: Discussionmentioning

confidence: 99%

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ZAK inhibits human lung cancer cell growth via ERK and JNK activation in an AP‐1‐dependent manner

Yang¹,

Lee²,

Hung

et al. 2010

Cancer Science

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Novel mixed-lineage kinase protein zipper sterile-a-motif kinase (ZAK) was first cloned by our laboratory. Lung cancer is the leading cause of cancer-related death in the world, including in Taiwan. Here, we wanted to investigate whether ZAK plays a potential role in lung cancer development. First, Western blot analysis results demonstrated that four cell lines expressed high levels of ZAK from among a panel of 10 lung cancer cell lines, and two of three normal lung cells expressed ZAK. ZAK gene expressions were down-regulated in lung cancers by real-time PCR analysis. Overexpression of ZAK suppressed cell proliferation in parallel with increased phosphorylated levels of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In contrast, ZAK silencing cells inhibited the expressions of phosphorylated ERK and JNK without affecting the expression of phosphorylated p38. The effect of the decreased cell growth rate was significantly but incompletely reversed when ZAK-overexpressing cells were treated with a specific ERK or JNK inhibitor. Moreover, c-Fos and c-Jun, the major downstream components of MAPKs, were up-regulated by ERK and JNK, respectively. When ZAK-overexpressing cells introduced with c-Jun RNA interference (RNAi), the activator protein-1 (AP-1) transcription activity detected by a secreted alkaline phosphatase (SEAP) assay was suppressed and the decreased cell number was reversed compared with the control RNAi-treated group. More importantly, ZAK significantly depressed tumor growth in in vivo study. Taken together, results from both in vitro and in vivo studies indicated that the decrease of lung cancer cell proliferation by ZAK may involve the ERK and JNK pathways via an AP-1 transcription factor. (Cancer Sci 2010; 101: 1374-1381 T he mixed-lineage kinases (MLKs) are a family of serine ⁄ threonine protein kinases that function as mitogen-activated protein kinase (MAPK) kinase kinases (MAPKKKs).(1)The MLKs cluster into three subgroups based on the domain arrangements and sequence similarity within their catalytic domains: the MLKs, the dual-leucine-zipper-bearing kinases, and zipper sterile-a-motif kinase (ZAK). We are the first group to clone ZAK in 2000(2) (GenBank accession number: AF238255). This cDNA has 2456 bp and encodes a protein of 800 amino acids that contains a kinase catalytic domain, a leucine zipper, and a sterile-a-motif (SAM). Our ZAK is also known as ZAK-a or MLK-like MAP triple kinase-a (MLTK-a).(1,3) ZAK-b is an alternative splicing product and is also referred to as MLTK-b or MLK7. ZAK-b is identical to ZAK-a from the amino terminus to the zipper domain, but then diverges and terminates shortly thereafter, so it lacks a SAM domain. (1,3) Similar to other MLK family members, the MLTKs regulate signaling of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase. The transcription factor activator protein-1 (AP-1) regulates a wide range of cellular processes, including cell proliferation, apoptosis, survival, and differe...

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Section: Discussionmentioning

confidence: 99%

“…(18)(19)(20)(21)(22)(23)(24)(25) In addition, there are several lines of evidence indicating that both ERK and JNK signaling pathways are involved in apoptotic process. (26)(27)(28)(29) In some cases, a decreased cell proliferation rate could be due to cell apoptosis. The above reports are, to a certain degree, in agreement with our results.…”

Section: Discussionmentioning

confidence: 99%

ZAK inhibits human lung cancer cell growth via ERK and JNK activation in an AP‐1‐dependent manner

Yang¹,

Lee²,

Hung

et al. 2010

Cancer Science

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“…In a human osteoblast cell line it was shown that citrinin induces apoptosis via activation of c-Jun Nterminal kinase (JNK), loss of mitochondrial membrane potential, and caspase-3 and p21-activated protein kinase 2 (PAK2) activation (Huang et al, 2009). In another study in human embryonic kidney (HEK293) and HeLa cells citrinin was shown to positively regulate ERK1/2 and JNK pathways as well as their downstream effectors; activated mitogen-activated protein kinases pathways were also involved in citrinin induced apoptosis (Chang et al, 2009). In human promyelocitic leukemia cells (HL-60) citrinin-induced apoptosis was characterized by the activation of caspase-3, -6, -7 and -9, but not caspase-8 (Yu et al, 2006).…”

Section: Modes Of Actionmentioning

confidence: 99%

Scientific Opinion on the risks for public and animal health related to the presence of citrinin in food and feed

2012

EFS2

164

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The European Food Safety Authority (EFSA) was asked by the European Commission to deliver a scientific opinion on the health risks from citrinin in food and feed. Citrinin is a mycotoxin produced by several species of the genera Aspergillus, Penicillium and Monascus and occurs mainly in stored grains. The available occurrence data were not adequate to carry out a dietary exposure assessment. Citrinin is nephrotoxic and a no‐observed‐adverse‐effect level (NOAEL) of 20 µg/kg body weight (b.w.) per day was identified from a 90‐day study in rats. Due to the limitations and uncertainties in the database, the derivation of a health‐based guidance value was not considered appropriate but a level of no concern for nephrotoxicity of 0.2 µg/kg b.w. per day was determined. Based on the available data a concern for genotoxicity and carcinogenicity could not be excluded at the level of no concern for nephrotoxicity. In the absence of adequate exposure data, characterisation of the risk of citrinin as a food contaminant was based on the estimate of the citrinin concentrations in grains and grain‐based products that would result in an exposure equal to the level of no concern for nephrotoxicity. For high consuming toddlers, other children and adults this citrinin concentration is between 9 and 53 µg citrinin/kg and between 19 and 100 µg citrinin/kg for average consumers, respectively. For animals, risk characterisation was based on the estimate of the citrinin concentration in grains that would result in exceedance of the NOAEL of 20 µg/kg b.w. per day for pigs, which ranged between 640 and 1 173 µg/kg. The CONTAM Panel concluded that the impact of uncertainties on the risk assessment is large, and more data regarding the toxicity and the occurrence of citrinin in food and feed in Europe are needed to enable refinement of the risk assessment.

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“…Lane 1, control; lane 2, 100 µg/ml ZPDC glycoprotein; lane 3, DEHP alone; lane 4, 25 µg/ml ZPDC glycoprotein in the presence of DEHP; lane 5, 50 µg/ml ZPDC glycoprotein in the presence of DEHP; lane 6, 100 µg/ml ZPDC glycoprotein in the presence of DEHP 503 zpdc glycoprotein inhibits cell proliferation chemically treated cells. 39 This means that the ZPDC glycoprotein indirectly prevents MAPK signaling via DEHP-stimulated PKCα activity.…”

Section: Discussionmentioning

confidence: 99%

“…* indicates significant differences between DEHP treatment and ZPDC glycoprotein treatment in the presence of DEHP, P < 0·05. Lane 39 This means that the ZPDC glycoprotein indirectly prevents MAPK signaling via DEHP-stimulated PKCα activity.…”

Section: Discussionmentioning

confidence: 99%

Plant‐originated glycoprotein (24 kDa) has an inhibitory effect on proliferation of BNL CL.2 cells in response to di(2‐ethylhexyl)phthalate

Liu

Lim

2011

Cell Biochemistry & Function

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Di(2-ethylhexyl)phthalate (DEHP) is one of the many environmental chemicals that are widely used in polyvinyl chloride products, vinyl flooring, food packaging and infant toys. They cause cell proliferation or dysfunction of human liver. The purpose of this study is to investigate the inhibitory effect of a glycoprotein (24 kDa) isolated from Zanthoxylum piperitum DC (ZPDC) on proliferation of liver cell in the DEHP-induced BNL CL. 2 cells. [³H]-thymidine incorporation, intracellular reactive oxygen species (ROS), intracellular Ca²⁺ mobilization and activity of protein kinase C (PKC) were measured using radioactivity and fluorescence method respectively. The expression of mitogen-activated protein kinases [extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)], activator protein (AP)-1 (c-Jun and c-Fos), proliferating cell nuclear antigen (PCNA) and cell cycle-related factors (cyclin D1/cyclin-dependent kinase [CDK] 4) were evaluated using Western blotting or electrophoretic mobility shift assay. The results in this study showed that the levels of [³H]-thymidine incorporation, intracellular ROS, intracellular Ca²⁺ mobilization and activity of PKCα were inhibited by ZPDC glycoprotein (100 µg/ml) in the DEHP-induced BNL CL. 2 cells. Also, activities of ERK, JNK and AP-1 were reduced by ZPDC glycoprotein (100 µg/ml). With regard to cell proliferation, activities of PCNA and cyclin D1/CDK4 were significantly suppressed at treatment with ZPDC glycoprotein (100 µg/ml) in the presence of DEHP. Taken together, these findings suggest that ZPDC glycoprotein significantly normalized activities of PCNA and cyclin D1/CDK4, which relate to cell proliferation factors. Thus, ZPDC glycoprotein appears to be one of the compounds derived from natural products that are able to inhibit cell proliferation in the phthalate-induced BNL CL. 2 cells.

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Activation of ERK and JNK signaling pathways by mycotoxin citrinin in human cells

Cited by 40 publications

References 43 publications

ZAK inhibits human lung cancer cell growth via ERK and JNK activation in an AP‐1‐dependent manner

ZAK inhibits human lung cancer cell growth via ERK and JNK activation in an AP‐1‐dependent manner

Scientific Opinion on the risks for public and animal health related to the presence of citrinin in food and feed

Plant‐originated glycoprotein (24 kDa) has an inhibitory effect on proliferation of BNL CL.2 cells in response to di(2‐ethylhexyl)phthalate

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