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题名:Granzyme B induction signalling pathway in acute myeloid leukemia cell lines stimulated by Tumor Necrosis Factor alpha and Fas Ligand ? ARTICLE
作者:Fabien Guilloton, Christine Jean, Aurlie de Thonel, Guy Laurent and Anne Quillet-Mary
来源:Cellular Signalling[IF=4.398], In Press, Corrected Proof, Available online 3 January 2007,
URL :http://dx.doi.org/10.1016/j.cellsig.2006.12.005
日期:070415
摘要: Fabien Guillotona, Christine Jeana, Aurlie de Thonelb, Guy Laurenta, c and Anne Quillet-Marya, ,

aINSERMU563/CPTP, Pavillon Lefebvre Bat B, Dpt G. DELSOL, Equipe G. LAURENT, CHU Purpan, 31024 Toulouse, France
bPresent address: Turku Centre for Biotechnology, Turku, Finland
cThe Service d Hmatologie, Centre Hospitalier Universitaire Purpan, Toulouse, 31059, France

Received 3 October 2006; revised 12 December 2006; accepted 14 December 2006. Available online 3 January 2007.

Summary

Acute myeloid leukemia (AML) cell lines treated by genotoxic agents or by Tumor Necrosis Factor alpha (TNF) 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 TNF- and FasL-stimulated AML cells. The effects of TNF and FasL on GrB expression were specifically mediated by p38MAPK (Mitogen-activated-protein-kinase) activation. Otherwise, TNF 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 TNF and FasL on GrB up regulation. Altogether, our results suggest that TNF- 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. 8ku 1:

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