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(1) 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.