Staurosporine resistance in inflammatory neutrophils is associated with the inhibition of caspase- and proteasome-mediated Mcl-1 degradation
Autor: | Christoph Peter, Michèle J. Hoffmann, Sascha Flohé, Sarah Lehmann, Klaus Unfried, Tamara Hornstein, Adnana Paunel-Görgülü, Denise Philipp, Joachim Windolf, Susanne Detmer, Sebastian Wesselborg |
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Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Programmed cell death Proteasome Endopeptidase Complex Myeloid Neutrophils Immunology Drug Resistance Apoptosis 03 medical and health sciences hemic and lymphatic diseases medicine Immunology and Allergy Staurosporine Humans Prospective Studies Enzyme Inhibitors Protein kinase B Caspase Inflammation biology Inflammation Extracellular Mediators & Effector Molecules Intrinsic apoptosis Cell Biology medicine.disease Cell biology Mitochondria Enzyme Activation Leukemia 030104 developmental biology medicine.anatomical_structure Case-Control Studies Caspases Proteolysis biology.protein Myeloid Cell Leukemia Sequence 1 Protein medicine.drug Signal Transduction |
Zdroj: | Journal of leukocyte biology. 99(1) |
ISSN: | 1938-3673 |
Popis: | Apoptosis resistance in activated neutrophils is known to be associated with collateral damage of surrounding tissue, as well as immune and organ dysfunction. Thus, the safe removal of neutrophils by apoptosis induction represents a prerequisite for the resolution of inflammation. Here, we report that intrinsic apoptosis resistance in human neutrophils, isolated from severely injured patients, is based on enhanced stabilization of antiapoptotic myeloid cell leukemia 1 and subsequent impairment of downstream apoptotic pathways. Whereas extrinsic apoptosis induction by the activation of Fas death receptor on inflammatory neutrophils was accompanied by caspase- and proteasome-mediated myeloid cell leukemia 1 degradation, intrinsic apoptosis induction by staurosporine led to a significant stabilization of myeloid cell leukemia 1 protein, which impeded on truncated forms of B cell lymphoma 2-associated X protein and B cell lymphoma 2 homology domain 3-interacting domain death translocation and subsequent cytochrome c release from the mitochondria. We show further that profound inhibition of myeloid cell leukemia 1 degradation is based on the inhibition of caspases and sustained activation of kinases involved in cell survival, such as Akt. Accordingly, impeded myeloid cell leukemia 1 phosphorylation on Ser159 by glycogen synthase kinase 3 and protein ubiquitination has been demonstrated. Inhibition of myeloid cell leukemia 1 activity markedly increased sensitivity to staurosporine-induced cell death. Altogether, these results provide new insights into the mechanisms underlying myeloid cell leukemia 1-mediated apoptosis resistance to staurosporine under inflammatory situations and should be considered for the development of novel therapeutic strategies. |
Databáze: | OpenAIRE |
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