c-Abl activation regulates induction of the SEK1/stress-activated protein kinase pathway in the cellular response to 1-beta-D-arabinofuranosylcytosine.
Previous work has shown that treatment of cells with the antimetabolite 1-beta-D-arabinofuranosylcytosine (ara-C) is associated with induction of the c-jun gene. The present studies demonstrate that ara-C activates the c-Abl non-receptor tyrosine kinase. We also demonstrate that activity of the stress-activated protein kinase (SAP kinase/JNK) is increased in ara-C-treated cells. Using cells deficient in c-Abl (Abl-/-) and after introduction of the c-abl gene, we show that ara-C-induced c-Abl activity is necessary for the stimulation of SAP kinase. Other studies using cells transfected with a SEK1 dominant negative demonstrate that ara-C-induced SAP kinase activity is SEK1-dependent. Furthermore, we show that overexpression of truncated c-Abl results in activation of the SEK1/SAP kinase cascade.
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
S
S
Kharbanda
P
P
Pandey
R
R
Ren
B
B
Mayer
L
L
Zon
D
D
Kufe
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D003561:Cytarabine / Q000494:pharmacology*; D004789:Enzyme Activation; D007700:Kinetics; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism; D011494:Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D014162:Transfection
D009842:Oligopeptides; D011994:Recombinant Proteins; D003561:Cytarabine; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases