PMID- 17258890 OWN - NLM STAT- MEDLINE DCOM- 20070724 LR - 20131121 IS - 0898-6568 (Print) IS - 0898-6568 (Linking) VI - 19 IP - 6 DP - 2007 Jun TI - Granzyme B induction signalling pathway in acute myeloid leukemia cell lines stimulated by tumor necrosis factor alpha and Fas ligand. PG - 1132-40 AB - Acute myeloid leukemia (AML) cell lines treated by genotoxic agents or by Tumor Necrosis Factor alpha (TNFalpha) acquire potent cytotoxicity towards myeloid cells through activation of granzyme B (GrB)/perforin (PFN) system. Here we first extend this observation to another death receptor activator, Fas Ligand (FasL). Moreover, we analyzed GrB induction signalling pathway in TNFalpha- and FasL-stimulated AML cells. The effects of TNFalpha and FasL on GrB expression were specifically mediated by p38MAPK (Mitogen-activated-protein-kinase) activation. Otherwise, TNFalpha and FasL stimulation led to radical oxygen species (ROS) generation and ASK1 (Apoptosis-signal-regulating-kinase-1) activation. Endogenous activation of ASK1 by either H2O2 or thioredoxin (Trx) reductase inhibition had the same effects as TNFalpha and FasL on GrB up regulation. Altogether, our results suggest that TNFalpha- and FasL-stimulated AML cell lytic induction is regulated by a signalling pathway involving sequentially, ROS generation, Trx oxidation, ASK1 activation, p38MAPK stimulation and GrB induction at mRNA and protein levels. FAU - Guilloton, Fabien AU - Guilloton F AD - INSERMU563/CPTP, Pavillon Lefebvre Bat B, Dpt G. DELSOL, Equipe G. LAURENT, CHU Purpan, 31024 Toulouse, France. FAU - Jean, Christine AU - Jean C FAU - de Thonel, Aurelie AU - de Thonel A FAU - Laurent, Guy AU - Laurent G FAU - Quillet-Mary, Anne AU - Quillet-Mary A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070103 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (Fas Ligand Protein) RN - 0 (Membrane Glycoproteins) RN - 0 (Pore Forming Cytotoxic Proteins) RN - 0 (RNA, Messenger) RN - 0 (Reactive Oxygen Species) RN - 0 (Tumor Necrosis Factor-alpha) RN - 126465-35-8 (Perforin) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5) RN - EC 2.7.11.25 (MAP3K5 protein, human) RN - EC 3.4.21.- (Granzymes) SB - IM MH - Animals MH - Cell Death/drug effects MH - Cell Line, Tumor MH - Enzyme Activation/drug effects MH - Enzyme Induction/drug effects MH - Fas Ligand Protein/*pharmacology MH - Gene Expression Regulation, Neoplastic/drug effects MH - Granzymes/*biosynthesis/*genetics/metabolism MH - Humans MH - Hydrogen Peroxide/pharmacology MH - Leukemia, Myeloid, Acute/*pathology MH - MAP Kinase Kinase Kinase 5/metabolism MH - Membrane Glycoproteins/metabolism MH - Mice MH - Perforin MH - Pore Forming Cytotoxic Proteins/metabolism MH - RNA, Messenger/genetics/metabolism MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/*drug effects MH - Tumor Necrosis Factor-alpha/*pharmacology MH - p38 Mitogen-Activated Protein Kinases/metabolism EDAT- 2007/01/30 09:00 MHDA- 2007/07/25 09:00 CRDT- 2007/01/30 09:00 PHST- 2006/10/03 00:00 [received] PHST- 2006/12/12 00:00 [revised] PHST- 2006/12/14 00:00 [accepted] PHST- 2007/01/30 09:00 [pubmed] PHST- 2007/07/25 09:00 [medline] PHST- 2007/01/30 09:00 [entrez] AID - S0898-6568(06)00339-1 [pii] AID - 10.1016/j.cellsig.2006.12.005 [doi] PST - ppublish SO - Cell Signal. 2007 Jun;19(6):1132-40. doi: 10.1016/j.cellsig.2006.12.005. Epub 2007 Jan 3.