7,12-Dimethylbenz[a]anthracene induces apoptosis in murine pre-B cells through a caspase-8-dependent pathway.
Polycyclic aromatic hydrocarbons (PAHs) have been demonstrated to cause a variety of tumors and immunosuppressive effects. Our laboratory, and others, have demonstrated that coculture of progenitor B lymphocytes (pre-B cells) with bone marrow stromal cells and the model PAH 7,12-dimethylbenz[a]anthracene (DMBA) results in pre-B cell apoptosis. In this study we investigated the molecular events that precede apoptosis in DMBA-treated 70Z/3 cells, a pre-B cell line. Using caspase activity assays and immunoblotting techniques, we determined the temporal pattern of caspase expression in the pre-B cells. Using caspase inhibitors, we demonstrated that DMBA-mediated pre-B cell apoptosis is dependent on activation of caspase-8, whereas caspase-9 activation is essential for maximal apoptosis. We also demonstrated that DMBA activated PKR, an interferon-inducible protein kinase, in pre-B cells. PKR in turn can activate caspase-8 independently of death receptor ligation. As a result of these studies, we propose a novel PKR-dependent pathway for activation of apoptosis in DMBA-treated pre-B cells.
Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin, USA.
Todd J
TJ
Page
Scott
S
O'Brien
Colin R
CR
Jefcoate
Charles J
CJ
Czuprynski
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051023:BH3 Interacting Domain Death Agonist Protein; D002273:Carcinogens / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002273:Carcinogens; D002352:Carrier Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015127:9,10-Dimethyl-1,2-benzanthracene; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases