title: Role of the JNK/c-Jun/AP-1 signaling pathway in galectin-1-induced T-cell death.
abstract: Galectin-1 (gal-1), an endogenous β-galactoside-binding protein, triggers T-cell death through several mechanisms including the death receptor and the mitochondrial apoptotic pathway. In this study we first show that gal-1 initiates the activation of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 4 (MKK4), and MKK7 as upstream JNK activators in Jurkat T cells. Inhibition of JNK activation with sphingomyelinase inhibitors (20 μM desipramine, 20 μM imipramine), with the protein kinase C-δ (PKCδ) inhibitor rottlerin (10 μM), and with the specific PKCθ pseudosubstrate inhibitor (30 μM) indicates that ceramide and phosphorylation by PKCδ and PKCθ mediate gal-1-induced JNK activation. Downstream of JNK, we observed increased phosphorylation of c-Jun, enhanced activating protein-1 (AP-1) luciferase reporter, and AP-1/DNA-binding in response to gal-1. The pivotal role of the JNK/c-Jun/AP-1 pathway for gal-1-induced apoptosis was documented by reduction of DNA fragmentation after inhibition JNK by SP600125 (20 μM) or inhibition of AP-1 activation by curcumin (2 μM). Gal-1 failed to induce AP-1 activation and DNA fragmentation in CD3-deficient Jurkat 31-13 cells. In Jurkat E6.1 cells gal-1 induced a proapoptotic signal pattern as indicated by decreased antiapoptotic Bcl-2 expression, induction of proapoptotic Bad, and increased Bcl-2 phosphorylation. The results provide evidence that the JNK/c-Jun/AP-1 pathway plays a key role for T-cell death regulation in response to gal-1 stimulation.Cell Death and Disease (2010) 1, e23; doi:10.1038/cddis.2010.1; published online 4 February 2010.
authors.affiliation: Medical Faculty, Department of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Brandt
authors.forename: E F
authors.initials: EF
authors.lastname: Abou-Eladab
authors.forename: M
authors.initials: M
authors.lastname: Tiedge
authors.forename: H
authors.initials: H
authors.lastname: Walzel
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D037483:Galectin 1 / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019169:Jurkat Cells; D007700:Kinetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000873:Anthracenes; D037483:Galectin 1; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051025:bcl-Associated Death Protein; C432165:pyrazolanthrone; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3; D053453:Caspase 9