p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death.
Heavy metals are important regulators of cell apoptosis. Manganese (Mn(2+)) 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+) was a potent apoptotic agent in human B cells, including lymphoma B cell lines. We show here that Mn(2+)-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+)-induced caspase-3 activation and apoptosis. Mn(2+)-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+)-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+)-induced apoptosis based on the sequential activation of p38 MAPK, MSK1, caspase-8 and mitochondria, respectively.
El Mchichi
B
B
INSERM, UMR 542, Université Paris-Sud, Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier, 94807 Villejuif, France.
Hadji
A
A
Vazquez
A
A
Leca
G
G
D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008345:Manganese / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D053200:Fas-Associated Death Domain Protein; D008345:Manganese; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8