TRANSIENT STIMULATION OF THE C-JUN-NH2-TERMINAL KINASE ACTIVATOR PROTEIN-1 PATHWAY AND INHIBITION OF EXTRACELLULAR SIGNAL-REGULATED KINASE ARE EARLY EFFECTS IN PACLITAXEL-MEDIATED APOPTOSIS IN HUMAN B-LYMPHOBLAST/

We demonstrate here that paclitaxel exposure to RPMI-1788 B lymphoblas ts caused a dose-and time-dependent increase in nuclear factor activat or protein 1 (AP-1) DNA binding activity, The basal DNA binding activi ties of nuclear factors NF-kappa B and Ets were not affected by paclit axel. Consistent with these biochemical events, paclitaxel stimulated AP-1-dependent chloramphenicol acetyltransferase (CAT) reporter gene t ranscription in vivo, as directed from a tetradecanoyl phorbol acetate -inducible promoter. AP-1 binding activity of nuclear extracts isolate d from paclitaxel treated cells was reduced following immunodepletion with antibodies directed against individual Jun family proteins, where as anti-cFos, anti-Fra1, and anti-FosB antibodies were not inhibitory. Paclitaxel caused a rapid and transient increase in c-Jun NH2-termina l kinase (JNK) activity, a proposed mediator of stress activation path ways. By contrast, exposure to paclitaxel produced a transient reducti on in the extracellular signal-regulated mitogen-activated protein kin ase 2 (ERK2) activity, a proposed mediator of growth factor-stimulated proliferation pathways. Transient activation of the c-Jun-NH2-termina l kinase/AP-1 pathway, together with down-regulation of ERK2 activity, may be a key event in the early response of RPMI-1788 B lymphoblasts to paclitaxel exposure.