Selective Activation in the MAPK Pathway by Hg(II) in Precision-Cut Rabbit Renal Cortical Slices

Turney, Karen D.; Parrish, Alan R.; Orozco, Jason; Gandolfi, A. Jay

doi:10.1006/taap.1999.8772

Cited by 20 publications

(7 citation statements)

References 29 publications

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“…The MAPK family includes the extracellular activated protein kinase (ERK 1/2), c‐Jun N ‐terminal kinase (JNK1/2), and 38 kDa kinase (p38 MAPK ), proteins whose function and regulation are well conserved from unicellular to complex organisms (Johnson and Lapadat, ). Activation of these kinases may occur in response to hyperosmotic stress, cytokine exposure, and toxic injury, including OS (Harper and LoGrasso, ; Kaminska, ) and metals, such as mercury, lead, and manganese, induce phosphorylation of MAPK in vertebrates (Turney et al, ; Posser et al, ). In Drosophila melanogaster , the MAPK pathway is known to be involved in numerous processes during normal development and in the regulation of immune response (Stronach and Perrimon, ), but until now, little has been known about the modulation of MAPK by toxins.…”

Section: Introductionmentioning

confidence: 99%

Effects of Hg(II) Exposure on MAPK Phosphorylation and Antioxidant System inD. melanogaster

et al. 2012

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The heavy metal mercury is a known toxin, but while the mechanisms involved in mercury toxicity have been well demonstrated in vertebrates, little is known about toxicological effects of this metal in invertebrates. Here, we present the results of our study investigating the effects associated with exposure of fruit fly Drosophila melanogaster to inorganic mercury (HgCl 2 ). We quantify survival and locomotor performance as well as a variety of biochemical parameters including antioxidant status, MAPK phosphorylation and gene expression following mercury treatment. Our results demonstrate that exposure to Hg(II) through diet induced mortality and affected locomotor performance as evaluated by negative geotaxis, in D. melanogaster. We also saw a significant impact on the antioxidant system including an inhibition of acetylcholinesterase (Ache), glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. We found no significant alteration in the levels of mRNA of antioxidant enzymes or NRF-2 transcriptional factor, but did detect a significant up regulation of the HSP83 gene. Mercury exposure also induced the phosphorylation of JNK and ERK, without altering p38 MAPK and the concentration of these kinases. In parallel, Hg(II) induced PARP cleavage in a 89 kDa fragment, suggesting the triggering of apoptotic cell death in response to the treatment. Taken together, this data clarifies and extends our understanding of the molecular mechanisms mediating Hg(II) toxicity in an invertebrate model. # 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 621-630, 2014.

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Section: Introductionmentioning

confidence: 99%

Effects of Hg(II) Exposure on MAPK Phosphorylation and Antioxidant System inD. melanogaster

et al. 2012

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“…(7) Studies of the three-dimensional structure of c-Src revealed that interaction between SH2 and phosphorylated Tyr527 together with SH3 and linker region folded the molecule in a closed, inactive state. (8,9) In addition to the Tyr527-based regulation, increasing evidence suggests that the c-Src kinase has a redox-linked regulatory mechanism.(10) One of the models of the redox-linked regulation, we found, is the activation of c-Src by mercuric chloride (HgCl 2 ).(11) Treatment of purified c-Src with mercuric chloride changed V max and K m of the kinase, suggesting the kinase activation to be a direct one.(11) Mercuric chloridetreatment of cells activates signal pathways leading to tyrosine phosphorylation of cellular proteins, (12) and activation of mitogenactivated protein (MAP) kinases, (13)(14)(15)(16) which in turn induce the expression of cytokines, (17) unregulated cell growth and DNA synthesis. (13,18) Consistently, treatment of c-Src with mercuric chloride activates the kinase.…”

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confidence: 99%

The cysteine‐cluster motif of c‐Src: Its role for the heavy metal‐mediated activation of kinase

et al. 2008

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We have previously reported that c-Src is activated by mercuric chloride (HgCl 2 ). We investigated the mechanism of this activation and found that in vitro activation of c-Src by HgCl 2 did not require tyrosine residues at 416 and 527. Both SH2 and SH3 domains of c-Src were dispensable for the activation by HgCl 2 . In contrast, iodoacetoamide (IAA) that binds to thiol side chain of cysteine blocked the activation of c-Src by HgCl 2 . To obtain more clues, each cysteine residue of c-Src was replaced with alanine. Of six cysteine residues in the kinase domain of c-Src, Cys483 and Cys498 located in the C-terminal portion as a cysteine-cluster (CC) motif were critical for the activation. In addition, other Src family kinases, Yes and Lyn, were activated by treatment with HgCl 2 , and cysteine residues, especially those correspond to Cys498 of Src in the CC motif of these kinases, were also required for the activation of the kinases by HgCl 2 . In addition to these observations, treatment of cells with HgCl 2 dramatically activated the wild-type c-Src, whereas it could not activate the mutant form of Src with a substitution of Cys498. Taken together, our results disclose that cysteine residues in the CC motif of c-Src, Cys483 and Cys498, act as a module for the activation of the kinase by a heavy metal compound, mercuric chloride. c -Src, a cellular counterpart of viral oncogene product, v-Src, is a non-receptor tyrosine kinase distributed widely in tissues.(1) Activation of c-Src is frequently observed in various human carcinomas including those of breast and colon carcinomas and is critical for their metastasis, (2) suggesting the importance of Src signaling in human malignant tumors. Regulation of kinase activity of c-Src has been well characterized. Phosphorylation of tyrosine 527 (Tyr527) located near the Cterminus appears to down-regulate the kinase. Point mutation of Tyr527 renders c-Src active and highly oncogenic, (3)(4)(5) whereas targeted disruption of C-terminal SRC kinase (CSK), (6) the kinase that phosphorylates Tyr527, caused activation of c-Src. (7) Studies of the three-dimensional structure of c-Src revealed that interaction between SH2 and phosphorylated Tyr527 together with SH3 and linker region folded the molecule in a closed, inactive state. (8,9) In addition to the Tyr527-based regulation, increasing evidence suggests that the c-Src kinase has a redox-linked regulatory mechanism.(10) One of the models of the redox-linked regulation, we found, is the activation of c-Src by mercuric chloride (HgCl 2 ).(11) Treatment of purified c-Src with mercuric chloride changed V max and K m of the kinase, suggesting the kinase activation to be a direct one.(11) Mercuric chloridetreatment of cells activates signal pathways leading to tyrosine phosphorylation of cellular proteins, (12) and activation of mitogenactivated protein (MAP) kinases, (13)(14)(15)(16) which in turn induce the expression of cytokines, (17) unregulated cell growth and DNA synthesis. (13,18) Consistently, treatment of c-Src with mercuric ...

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“…One of the important mechanisms regulating AP-1 activity is phosphorylation of Ser 63 and Ser 73 residues in the N-terminal part of c-Jun protein that controls the transacting activity of the AP-1 complex [17]. c-Jun N-terminal kinases (JNK) are major if not the only type of kinases phosphorylating Ser 63 and Ser 73 residues in c-Jun [18, 19]and are activated in cells exposed to various stresses, including heavy metal ions [20, 21, 22, 23, 24]. It has been reported that antigen-mediated mast cell activation is associated with an increase in JNK activity [25], and inactivation of gene for MEKK 2, the upstream kinase-regulating JNK, prevented antigen-mediated IL-4 expression in these cells [26].…”

Section: Introductionmentioning

confidence: 99%

c-Jun N-Terminal Kinase Is Involved in Mercuric Ions-Mediated Interleukin-4 Secretion in Mast Cells

Walczak‐Drzewiecka¹,

Wyczółkowska²,

Dastych³

2005

Int Arch Allergy Immunol

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Background: Interleukin (IL)-4 plays a prominent role in immune response. Mercuric compounds upregulate IL-4 expression in animal tissues, and this upregulation plays a role in mercuric-mediated immunomodulation. Mercuric ions-mediated IL-4 expression was observed in vitro in T lymphocytes and mast cells. In the present study, we investigated molecular mechanisms responsible for this effect of mercuric ions in mast cells. Methods: C1.MC/C57.1 mouse mast cells were exposed in vitro to increasing concentrations of Hg²⁺ in the absence or presence of the specific c-Jun N-terminal kinase (JNK) inhibitor SP600125. The level of phosphorylated c-Jun in mast cells was determined by Western blotting, JNK activity assessed with in vitro kinase assay and the amount of secreted IL-4 determined by ELISA. Results: We observed that Hg²⁺ upregulated c-Jun phosphorylation on Ser 73 at concentrations which overlapped concentrations mediating IL-4 secretion. Phosphorylation of c-Jun in mast cells was associated with an increase in JNK activity. The specific JNK inhibitor SP600125 abolished both mercuric-induced c-Jun phosphorylation and IL-4 secretion in mast cells. Conclusions: These observations are consistent with the hypothesis that JNK is one of the signaling proteins mediating the effect of Hg²⁺ on IL-4 expression in mast cells and is engaged in environmentally mediated immunomodulation.

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Selective Activation in the MAPK Pathway by Hg(II) in Precision-Cut Rabbit Renal Cortical Slices

Cited by 20 publications

References 29 publications

Effects of Hg(II) Exposure on MAPK Phosphorylation and Antioxidant System inD. melanogaster

Effects of Hg(II) Exposure on MAPK Phosphorylation and Antioxidant System inD. melanogaster

The cysteine‐cluster motif of c‐Src: Its role for the heavy metal‐mediated activation of kinase

c-Jun N-Terminal Kinase Is Involved in Mercuric Ions-Mediated Interleukin-4 Secretion in Mast Cells

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