Lead Activates Nuclear Transcription Factor -κB, Activator Protein-1, and Amino-Terminal c-Jun Kinase in Pheochromocytoma Cells

Ramesh, Govindarajan T.; Manna, Sunil K.; Aggarwal, Bharat B.; Jadhav, Arun L.

doi:10.1006/taap.1999.8624

Cited by 77 publications

(28 citation statements)

References 32 publications

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“…Data presented in this report confirms this idea in chondrocytes by demonstrating that lead significantly inhibits basal NF-KB activity while potentiating the effect of PTHrP on AP-1 signaling. The stimulatory effect of lead on PTHrP-induced AP-1 activity is in agreement with at least one other report describing the activationlpotentiation of AP-1 by lead in pheochromocytoma (PC-I 2) cells [33]. However, the inhibitory effect of lead on NF-KB contrasts with earlier data indicating that lead activates this pathway in PC-12 cells and other cell types (reviewed in [21]).…”

Section: Discussionsupporting

confidence: 90%

“…It is generally held that many of lead's effects are dependent on its ability to substitute for calcium and zinc in the metal binding domains of various kinases and transcription factors. Documented targets include calmodulin [20,29], ERWMAPK [48], MEK, J N K and AP-1 [33], calcium channels [32,42], and NF-KB [21], where lead activates or potentiates signaling activity either directly or indirectly. The significant impact of lead on skeletal development and bone growth implies that its toxic effects are borne out in the growth plate, where normal proliferation and differentiation of chondrocytes may be impaired.…”

Section: Discussionmentioning

confidence: 99%

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Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Zuscik

Pateder

Puzas

et al. 2002

Journal Orthopaedic Research

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The skeletal system is an important target for lead toxicity. One of the impacts of lead in the skeleton, the inhibition of axial bone development, is likely due to its effect on the normal progression of chondrocyte maturation that is central to the process of endochondral ossification, Since little is known about the effect of lead on chondrocyte function/maturation, its impact on ( I ) growth factor-induced proliferation, (2) expression of maturation-specific markers type X collagen and BMP-6, and (3) the activity of AP-1 and NF-KB was examined in chick growth plate and sternal chondrocyte models. Exposure to lead alone (1-30 pM) resulted in a dose-dependent inhibition of thymidine incorporation in growth plate chondrocytes. Lead also blunted the stimulation of thymidine incorporation by parathyroid hormone-related peptide (PTHrP) and transforming growth factor-Dl (TGF-PI), two critical regulators of chondrocyte maturation. Lead (1 and 10 pM), TGF-01 (3 ng/ml) and PTHrP (lo-' M) all significantly inhibited the expression of type X collagen, a marker of chondrocyte terminal differentiation. However, when in combination, lead completely reversed the inhibition of rype X collagen by PTHrP and TGF-01. The effect of lead on BMP-6, an inducer of terminal differentiation, was also examined. Independently, lead and TGF-PI were without effect on BMP-6 expression, but PTHrP significantly suppressed it. Comparatively, lead did not alter PTHrP-mediated suppression of BMP-6, but in combination with TGF-PI, BMP-6 expression was increased 3-fold. To determine if lead effects on signaling might play a role in facilitating these events, the impact of lead on NF-tiB and AP-1 signaling was assessed using luciferase reporter constructs in sternal chondrocytes. Lead had no effect on the AP-1 reporter, but it dose-dependently inhibited the NF-tiB reporter. PTHrP, which signals through AP-1, did not activate the NF-KB reporter and did not affect inhibition of this reporter by lead. In contrast, PTHrP activation of the AP-1 reporter was dosedependently enhanced by lead. These findings, which establish that chondrocytes are important targets for lead toxicity, suggest that the effects of lead on bone growth are derived from its impact on the modulation of chondrocyte maturation by growth factors and second messenger signaling responses.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Zuscik

Pateder

Puzas

et al. 2002

Journal Orthopaedic Research

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“…Certain other studies have shown that exposure to arsenic induced basal NF-B binding activity but without an increase in IB␣ phosphorylation nor an increase in translocation in lung epithelial cells and alveolar macrophages indicating alternative mechanism [43,80]. We have reported earlier from our laboratory that metals such as lead and manganese (Mn 2+ ) have also induced NF-B activation and corresponding degradation of IB␣ in PC12 cells, a dopaminergic cell line [81,64].…”

Section: Discussionmentioning

confidence: 84%

Low levels of arsenite activates nuclear factor‐κB and activator protein‐1 in immortalized mesencephalic cells

Kumar

Manna

Wise

et al. 2005

J Biochem & Molecular Tox

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Degeneration of dopaminergic neurons is one of the major features of Parkinson's disease. Many redox-active metals such as iron and manganese have been implicated in neuronal degeneration characterized by symptoms resembling Parkinson's disease. Even though, arsenic, which is another redox-active metal, has been shown to affect the central monoaminergic systems, but its potential in causing dopaminergic cell degeneration has not been fully known. Hence, the present study was designed to investigate arsenic signaling especially that is mediated by reactive oxygen species and its effect on early transcription factors in dopamine producing mesencephalic cell line 1RB3AN27. These mesencephalic cells were treated with low concentrations of sodium arsenite (0.1, 0.5, 1, 5, and 10 microM) and incubated for different periods of time (0-4 h). Arsenite was cytotoxic at 5 and 10 microM concentrations only after 72-h incubation period. Arsenite, in a dose-dependent manner, induced generation of reactive oxygen species (ROS) and activation of early transcription factors such as nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) as shown by electro mobility shift assay. Incubation of antioxidants, either N-acetyl-L-cysteine (50 microM) or alpha-tocopherol (50 microM) with 1 microM arsenite, suppressed ROS generation. Arsenite at 1 microM concentration was sufficient for maximal activation of NF-kappaB and AP-1 activation. Time kinetics studies showed maximal activation of NF-kappaB by 1 microM concentration of arsenite was seen at 120 min and correlated with complete degradation of Ikappa Balpha at 60 min. Similarly, maximal activation of AP-1 by 1 microM concentration of arsenite occurred at 120 min. N-acetyl-L-cysteine at 50 microM concentration inhibited arsenite-induced NF-kappa B and AP-1. In addition, arsenite was shown to induce phosphorylation of extracellular signal regulated kinase (ERK) 1/2 at concentrations of 1 microM and above. These results suggest that arsenite, at low and subcytoxic concentrations, appears to induce oxidative stress leading to activation of early transcription factors whereas addition of antioxidant inhibited the activation of these factors.

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“…Activation of MEK and MAPK by lead had been previously found in PC12 cells (Ramesh et al, 1999) but was not studied in the context of cell proliferation. Our results suggest that by activating the ERK1/2 pathway, lead may act as a tumor promoter in transformed glial cells, although such findings may not extend to other cell types.…”

Section: Discussionmentioning

confidence: 99%

Inorganic Lead Activates the Mitogen-Activated Protein Kinase Kinase-Mitogen-Activated Protein Kinase-p90^RSK Signaling Pathway in Human Astrocytoma Cells via a Protein Kinase C-Dependent Mechanism

Lu¹,

Guizzetti²,

Costa³

2002

J Pharmacol Exp Ther

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We have previously reported that lead acetate activates protein kinase C␣ (PKC␣) and induces DNA synthesis in human 1321N1 astrocytoma cells. In this study, we investigated the ability of lead to activate the mitogen-activated protein kinase (MAPK) cascade. We found that exposure to lead acetate (1-50 M) resulted in concentration-and time-dependent activation of MAPK (extracellular signal responsive kinase 1/2), as shown by increased phosphorylation and increased kinase activity. This effect was significantly reduced by the PKC-specific inhibitor bisindolylmaleimide (GF109203X), by down-regulation of PKC with 12-O-tetradecanoyl-phorbol 13-acetate, by a pseudosubstrate to PKC␣, and by selective down-regulation of PKC␣ by prior lead exposure.Lead was also shown to activate MAPK kinase (MEK1/2), and this effect was mediated by PKC. Two MEK inhibitors, 2-(2Ј-amino-3Ј-methoxyphenol)-oxanaphthalen-4-one (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (UO126), blocked lead-induced MAPK activation and inhibited lead-induced DNA synthesis, as measured by incorporation of [methyl-3 H]thymidine into cell DNA. The 90 kDa ribosomal S6 protein kinase, p90 RSK

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Lead Activates Nuclear Transcription Factor -κB, Activator Protein-1, and Amino-Terminal c-Jun Kinase in Pheochromocytoma Cells

Cited by 77 publications

References 32 publications

Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Low levels of arsenite activates nuclear factor‐κB and activator protein‐1 in immortalized mesencephalic cells

Inorganic Lead Activates the Mitogen-Activated Protein Kinase Kinase-Mitogen-Activated Protein Kinase-p90^RSK Signaling Pathway in Human Astrocytoma Cells via a Protein Kinase C-Dependent Mechanism

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Lead Activates Nuclear Transcription Factor -κB, Activator Protein-1, and Amino-Terminal c-Jun Kinase in Pheochromocytoma Cells

Cited by 77 publications

References 32 publications

Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Low levels of arsenite activates nuclear factor‐κB and activator protein‐1 in immortalized mesencephalic cells

Inorganic Lead Activates the Mitogen-Activated Protein Kinase Kinase-Mitogen-Activated Protein Kinase-p90RSK Signaling Pathway in Human Astrocytoma Cells via a Protein Kinase C-Dependent Mechanism

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Inorganic Lead Activates the Mitogen-Activated Protein Kinase Kinase-Mitogen-Activated Protein Kinase-p90^RSK Signaling Pathway in Human Astrocytoma Cells via a Protein Kinase C-Dependent Mechanism