title: Up-regulation of Bak and Bim via JNK downstream pathway in the response to nitric oxide in human glioblastoma cells.
abstract: Nitric oxide (NO) is a chemical messenger implicated in neuronal damage associated with ischemia neurodegenerative disease and excitotoxicity. In the present study, we examined the biological effects of NO and its mechanisms in human malignant glioblastoma cells. Addition of a NO donor, S-nitroso-N-acetyl-penicillamine (SNAP), induced apoptosis in U87MG human glioblastoma cells, accompanied by opening mitochondrial permeability transition pores, release of cytochrome c and AIF, and subsequently by caspase activation. NO-induced apoptosis occurred concurrently with significantly increased levels of the Bak and Bim. Treatment with SNAP resulted in sustained activation of JNK and its downstream pathway, c-Jun/AP-1. The expression of dominant-negative (DN)-JNK1 and DN-c-Jun suppressed the activation of AP-1, the induction of Bak and Bim, and the SNAP-induced apoptosis. In addition, de novo protein synthesis was required for the initiation of apoptosis in that the protein synthesis inhibitor, cycloheximide (CHX), inhibited NO-induced apoptotic cell death as well as up-regulation of Bak and Bim. These results suggest that NO activates an apoptotic cascade, involving sustained JNK activation, AP-1 DNA binding activity, and subsequent Bak and Bim induction, followed by cytochrome c and AIF releases and caspases cascade activation, resulting in human malignant brain tumor cell death.
authors.affiliation: Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, Korea.
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Hyung-Chahn
authors.initials: HC
authors.lastname: Lee
authors.forename: Sang-Hyeok
authors.initials: SH
authors.lastname: Woo
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Hong
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Doo-Hyun
authors.initials: DH
authors.lastname: Yoo
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Rhee
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; C110881:S-nitro-N-acetylpenicillamine; D050998:bcl-2 Homologous Antagonist-Killer Protein; D009569:Nitric Oxide; D048670:MAP Kinase Kinase 4; D010396:Penicillamine