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Caspase Inhibition Blocks Cell Death and Results in Cell Cycle Arrest in Cytokine-deprived Hematopoietic Cells

Brown, Nicholas M. ; Martin, Sean M. ; Maurice, Nick ; Kuwana, Tomomi ; Knudson, C. Michael

The Journal of biological chemistry, 2007-01, Vol.282 (4), p.2144-2155 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Caspase Inhibition Blocks Cell Death and Results in Cell Cycle Arrest in Cytokine-deprived Hematopoietic Cells
Autor: Brown, Nicholas M. ; Martin, Sean M. ; Maurice, Nick ; Kuwana, Tomomi ; Knudson, C. Michael
Assuntos: Amino Acid Chloromethyl Ketones - pharmacology ; Animals ; Apoptosis - drug effects ; B-Lymphocytes - cytology ; B-Lymphocytes - physiology ; bcl-2-Associated X Protein - physiology ; Caspase Inhibitors ; Cell Cycle - drug effects ; Cell Differentiation ; Cell Line ; Cytochrome c Group - physiology ; Enzyme Activation ; Enzyme Inhibitors - pharmacology ; Hematopoiesis ; Hematopoietic System - physiology ; Humans ; Interleukin-3 - deficiency ; Interleukin-3 - pharmacology ; Mice ; Quinolines - pharmacology
É parte de: The Journal of biological chemistry, 2007-01, Vol.282 (4), p.2144-2155
Notas: http://www.jbc.org/
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Descrição: Cytokine deprivation has been classically used to study molecular processes of apoptosis. Following interleukin (IL)-3 withdrawal in FL5.12 cells, Bax undergoes a conformational change that results in its mitochondria targeting, cytochrome c release, activation of caspase-9, and apoptosis. Cells overexpressing Casp9DN (dominant negative caspase-9) or treated with the caspase inhibitor Q-VD-OPh increased viability but failed to increase clonogenic survival. We find that caspase-inhibited cells had a significant fraction of viable cells (herein termed “rescued” cells) that failed to initiate cell division after IL-3 add back. The “rescued” cells had reduced mitochondrial potential, stained for active Bax, and had reduced staining with dihydroethidium, an agent sensitive to superoxide levels. Readdition of IL-3 after deprivation demonstrated that Bax activation was reversed, whereas altered 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide and dihydroethidium staining persisted for days. Furthermore, the “rescued” cells were resistant to rotenone, an inhibitor of mitochondrial respiration. The cells were highly sensitive to 2-deoxyglucose, an inhibitor of glycolysis and proposed anti-cancer agent. We conclude that the inhibition of caspase-9 allows cells to retain viability, but cells have prolonged mitochondrial dysfunction and enter a unique nondividing state that shares some properties with malignant cells.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Caspase Inhibition Blocks Cell Death and Results in Cell Cycle Arrest in Cytokine-deprived Hematopoietic Cells

Brown, Nicholas M. ; Martin, Sean M. ; Maurice, Nick ; Kuwana, Tomomi ; Knudson, C. Michael

United States: Elsevier Inc

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