Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2

Schrantz, Nicolas; Blanchard, Dominique; Mitenne, F; Auffredou, Marie Thérèse; Vázquez, Aimé; Leca, Gérald

doi:10.1038/sj.cdd.4400508

Cited by 61 publications

(54 citation statements)

References 59 publications

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“…We initially reported that Mn 2 þ apoptosis in lymphoma B cell was caspase-3-dependent. 5 Other groups reported similar results using other cell types. 3,22 Nevertheless, the pathway responsible for caspase-3 activation remains unclear.…”

Section: Resultsmentioning

confidence: 54%

“…The kinetics of activation was faster than for BL41. Ectopic overexpression of Bcl-2 in Ramos B cells (Ramos/Bcl-2) rendered these cells resistant to Mn 2 þ -mediated apoptosis 5 (Figure 3b). Mitochondrial activation, as measured by DCM loss and Cyt c release, was inhibited in Ramos/Bcl-2 cells, and this inhibition was also associated with an inhibition of Mn 2 þ -induced caspase-3 activation.…”

Section: Resultsmentioning

confidence: 99%

“…19 We previously showed that Mn 2 þ induced apoptosis in human B cells. 5 This cell death was caspase-3-dependent and was inhibited by overexpression of Bcl-2 protein. 5,20 We also showed that zinc, another divalent cation, exerted the opposite effect in human B lymphoma cells.…”

mentioning

confidence: 99%

“…5 This cell death was caspase-3-dependent and was inhibited by overexpression of Bcl-2 protein. 5,20 We also showed that zinc, another divalent cation, exerted the opposite effect in human B lymphoma cells. 20 At low concentrations (o50 mM), zinc inhibited the loss of mitochondrial membrane potential (DCM) and the activation of both caspase-9 and caspase-3 associated with apoptosis induced by Mn 2 þ .…”

mentioning

confidence: 99%

“…1 High concentrations of Mn 2 þ can provoke a series of intracellular molecular events that lead to apoptosis. [2][3][4][5] The mechanism by which Mn 2 þ induces cell death is somewhat controversial and not well understood. Several lines of evidence suggest that treatment of cells by Mn 2 þ induces different cellular changes, depending on the cell types studied.…”

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confidence: 99%

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p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death

et al. 2007

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Heavy metals are important regulators of cell apoptosis. Manganese (Mn 2 þ ) is a potent inducer of apoptosis in different cell types, but the precise mechanisms that mediate such effects are not well defined. We previously reported that Mn 2 þ was a potent apoptotic agent in human B cells, including lymphoma B cell lines. We show here that Mn 2 þ -induced cell death in human B cells is associated with caspase-8-dependent mitochondrial activation leading to caspase-3 activity and apoptosis. We used specific caspase-8 interfering shRNAs to reduce caspase-8 expression, and this also reduced Mn 2 þ -induced caspase-3 activation and apoptosis. Mn 2 þ -triggered caspase-8 activation is associated with a specific pathway, which is independent of Fas-associated death domain protein, and dependent on the sequential activation of p38-mitogen-activated protein kinase (p38 MAPK) and mitogen-and stress-response kinase 1 (MSK1). Inhibition of p38 activity using either pharmacological inhibitors or dominant-negative mutant forms of p38 blocked Mn 2 þ -mediated phosphorylation of MSK1 and blocked subsequent caspase-8 activation. However, specific inhibitors and the expression of a dominant-interfering mutant of MSK1 only inhibited caspase-8 activation, but not p38 activity. These findings suggest a novel model for the regulation of caspase-8 during Mn 2 þ -induced apoptosis based on the sequential activation of p38 MAPK, MSK1, caspase-8 and mitochondria, respectively.

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Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death

et al. 2007

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Manganese-induced rat pheochromocytoma (PC12) cell death is independent of caspase activation

et al. 2000

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Effect of the iron chelator desferrioxamine on manganese‐induced toxicity of rat pheochromocytoma (PC12) cells

Roth

Feng

Dolan

et al. 2002

J of Neuroscience Research

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Alterations in iron levels are likely to influence the biological actions of Mn in PC12 cells, because both metals are transported via the divalent metal transporter 1 (DMT1; also Nramp2 or DCT1). Studies were performed to determine the effect of the iron chelator desferrioxamine (DfO) on Mn-induced PC12 cell death and neuronal differentiation. Cell death almost doubled when PC12 cells were exposed for 24 hr to both DfO (10 microM) and Mn (0.3 mM) as opposed to Mn alone. DfO also stimulated Mn-induced neuronal differentiation by enhancing the phosphorylation of both ERK1 and 2 and also attenuated the increase in caspase 3-like activity induced by 0.3 mM Mn by approximately 50%, indicating that caspase activation, as reported previously, does not contribute to Mn-induced PC12 cell death. DfO also affected Mn-induced suppression of mitochondrial function as indicated by an additional 16% loss of ATP formation in PC12 cells cotreated with 0.3 mM Mn. Because sequestration of iron by DfO would be expected to lead to increased transport of Mn, studies were performed to determine whether iron inhibited Mn transport in PC12 cells. Iron inhibited 54Mn transport with an IC50 of approximately 20 microM. In addition, coincubation of DfO with Mn in PC12 cells resulted in increased expression of both the iron response element-positive and the iron response element-negative forms of DMT1. Taken together, these results demonstrate that iron status is likely to have a direct effect on the uptake and biological actions of Mn and probably other divalent metals that are transported by DMT1.

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Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2

Cited by 61 publications

References 59 publications

p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death

p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death

Manganese-induced rat pheochromocytoma (PC12) cell death is independent of caspase activation

Effect of the iron chelator desferrioxamine on manganese‐induced toxicity of rat pheochromocytoma (PC12) cells

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