Role of c-Jun N-terminal kinase/p38 stress signaling in 1-β- d-arabinofuranosylcytosine-induced apoptosis

1-β- d-Arabinofuranosylcytosine (ara-C) induced apoptosis in HL-60 cells, which was preceded by the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK). 2′-Amino-3′-methoxyflavo...

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Bibliographic Details
Published in:Biochemical pharmacology 2000-02, Vol.59 (4), p.407-418
Main Authors: Stadheim, Terrance A, Saluta, Gilda R, Kucera, Gregory L
Format: Article
Language:English
Subjects:
1-β- d-arabinofuranosylcytosine
Antineoplastic agents
apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Biological and medical sciences
Cytarabine - pharmacology
Enzyme Inhibitors - pharmacology
ERK
General aspects
HL-60 Cells
Humans
JNK
JNK Mitogen-Activated Protein Kinases
Medical sciences
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - physiology
p38
p38 Mitogen-Activated Protein Kinases
PD098059
Pharmacology. Drug treatments
SAPK
SB203580
Signal Transduction - drug effects
Transfection
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Summary:1-β- d-Arabinofuranosylcytosine (ara-C) induced apoptosis in HL-60 cells, which was preceded by the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK). 2′-Amino-3′-methoxyflavone (PD098059) and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1 H-imidazole (SB203580) were used to inhibit the activity of ERK and p38, respectively. SEK-AL, a dominant-negative mutant of SEK1, was transfected into HL-60 cells (HL-60/SEK-AL) to assess the role of JNK/SAPK activity in apoptosis. PD098059 (25 μM) inhibited ara-C-induced caspase-3-like activity but was ineffective in altering ara-C-mediated apoptotic DNA fragmentation and clonogenicity. On the other hand, SB203580 (20 μM) inhibited ara-C-induced caspase-3-like activity, apoptotic DNA fragmentation, and clonogenicity. The inhibition of JNK1 activation in HL-60/SEK-AL cells did not block ara-C-induced apoptotic DNA fragmentation. These results suggest that ara-C-induced apoptotic DNA fragmentation and loss of clonogenicity occur through a p38-dependent pathway.
ISSN:0006-2952
1873-2968
DOI:10.1016/S0006-2952(99)00330-5