title: CoCl2 induces apoptosis through the mitochondria- and death receptor-mediated pathway in the mouse embryonic stem cells.
abstract: Embryonic hypoxia/ischemia is a major cause of a poor fetal outcome and future neonatal and adult handicaps. However, biochemical cellular events in mouse embryonic stem (mES) cells during hypoxia remains unclear. This study investigated the underlying mechanism of apoptosis in mES cells under CoCl2-induced hypoxic/ischemic conditions. CoCl2 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and the accumulation of reactive oxygen species in mES cells. The CoCl2-treated mES cells showed a decrease in cell viability as well as typical apoptotic changes, cell shrinkage, chromatin condensation, and nuclear fragmentation and an extended G2/M phase of the cell cycle. CoCl2 augmented the release of cytochrome c into the cytosol from the mitochondria with a concomitant loss of the mitochondrial transmembrane potential (ΔΨm) and upregulated the voltage-dependent anion channel. In addition, CoCl2-induced caspase-3, -8, and -9 activation and upregulation of p53 level, whereas downregulated Bcl-2 and Bcl-xL, a member of the anti-apoptotic Bcl-2 family in mES cells. Furthermore, CoCl2 led to the upregulation of Fas and Fas-ligand, which are the death receptor assemblies, as well as the cleavage of Bid in mES cells. These results suggest that CoCl2 induces apoptosis through both mitochondria- and death receptor-mediated pathways that are regulated by the Bcl-2 family in mES cells.
authors.affiliation: Research Center for Biomineralization Disorder, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, South Korea.
authors.forename: Jin-Ha
authors.initials: JH
authors.lastname: Lee
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Min-Woo
authors.initials: MW
authors.lastname: Baek
authors.forename: Mi-Hwa
authors.initials: MH
authors.lastname: Kim
authors.forename: Heong-Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sun-Hun
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Won-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Jung
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000502:physiology*; D053222:Fas Ligand Protein / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C052617:Bcl2 protein, mouse; D003035:Cobalt; D045304:Cytochromes c; D020169:Caspases; C018021:cobaltous chloride