title: Differential regulation of the mitochondrial and death receptor pathways in neural stem cells.
abstract: Despite an increasing interest in neural stem cell (NSC) research, relatively little is known about the biochemical regulation of cell death pathways in these cells. We demonstrate here, using murine-derived multipotent C17.2 NSCs, that cells undergo mitochondria-mediated cell death in response to apoptotic stimuli such as oxidative stress induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). In particular, treated cells exhibited apoptotic features, including Bax translocation, cytochrome c release, activation of caspase-9 and -3, chromatin condensation and DNA fragmentation. Although C17.2 cells possess the Fas receptor and express procaspase-8, agonistic Fas mAb treatment failed to induce apoptosis. Fas treatment activated the extracellular signal-regulated protein kinase (ERK) pathway, which may have an antiapoptotic as well as a growth stimulating role. Combined, our findings indicate that while NSCs are sensitive to cytotoxic stimuli that involve an engagement of mitochondria, Fas treatment does not induce death and may have an alternative role.
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, 71 77 Stockholm, Sweden.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Tamm
authors.forename: John D
authors.initials: JD
authors.lastname: Robertson
authors.forename: Eric
authors.initials: E
authors.lastname: Sleeper
authors.forename: Mari
authors.initials: M
authors.lastname: Enoksson
authors.forename: Mia
authors.initials: M
authors.lastname: Emgård
authors.forename: Sten
authors.initials: S
authors.lastname: Orrenius
authors.forename: Sandra
authors.initials: S
authors.lastname: Ceccatelli
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001562:Benzimidazoles / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004347:Drug Interactions; D016521:Electrophoresis, Gel, Pulsed-Field / Q000379:methods; D004791:Enzyme Inhibitors / Q000633:toxicity; D005419:Flavonoids / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011419:Propidium / Q000378:metabolism; D019311:Staurosporine / Q000633:toxicity; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D061945:Caspase Inhibitors; D002843:Chromatin; D003374:Coumarins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D009285:Naphthoquinones; D009842:Oligopeptides; C102580:acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; D019014:fas Receptor; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; D011419:Propidium; C063002:2,3-dimethoxy-1,4-naphthoquinone; D045304:Cytochromes c; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D019311:Staurosporine; C017807:bisbenzimide ethoxide trihydrochloride; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one