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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 Lymphoblasts¹

Department of Biology, Boston College, Chestnut Hill, Massachusetts 02167 [S. F. A., J. M. S., T. C. C.], and the Department of Surgery, Roger Williams Medical Center, Brown University, Providence, Rhode Island 02908 [M. B., H. J. W., S. R. M.]

We demonstrate here that paclitaxel exposure to RPMI-1788 B lymphoblasts caused a dose- and time-dependent increase in nuclear factor activator protein 1 (AP-1) DNA binding activity. The basal DNA binding activities of nuclear factors NF-B and Ets were not affected by paclitaxel. Consistent with these biochemical events, paclitaxel stimulated AP-1-dependent chloramphenicol acetyltransferase (CAT) reporter gene transcription in vivo, as directed from a tetradecanoyl phorbol acetate-inducible promoter. AP-1 binding activity of nuclear extracts isolated from paclitaxel treated cells was reduced following immunodepletion with antibodies directed against individual Jun family proteins, whereas anti-cFos, anti-Fra1, and anti-FosB antibodies were not inhibitory. Paclitaxel caused a rapid and transient increase in c-Jun NH₂-terminal kinase (JNK) activity, a proposed mediator of stress activation pathways. By contrast, exposure to paclitaxel produced a transient reduction in the extracellular signal-regulated mitogen-activated protein kinase 2 (ERK2) activity, a proposed mediator of growth factor-stimulated proliferation pathways. Transient activation of the c-Jun-NH₂-terminal 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.

¹ This work was supported by USPHS Grants AI-34586 to (T. C. C.) and ES-05970 to (S. R. M.). The laboratories of both principal investigators (T. C. C. and S. R. M.) contributed equally to the experiments reported in this study.

² These authors contributed equally to the experiments herein and share first authorship.

³ To whom requests for reprints should be addressed, at Department of Biology, 411 Higgins Hall, Boston College, Chestnut Hill, MA 02167. Phone: (617) 552-0840; Fax: (617) 552-2011; E-mail: thomas.chiles@bc.edu.

Received 3/18/97. Accepted 11/13/97.

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