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First published on February 9, 2005; DOI: 10.1124/mol.104.004234

0026-895X/05/6705-1684-1689$20.00
Mol Pharmacol 67:1684-1689, 2005

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ORIGINAL ARTICLE

Cephalostatin 1 Inactivates Bcl-2 by Hyperphosphorylation Independent of M-Phase Arrest and DNA Damage

Irina M. Müller, Verena M. Dirsch, Anita Rudy, Nancy López-Antón, George R. Pettit, and Angelika M. Vollmar

Department of Pharmacy, Center of Drug Research, University of Munich, Munich, Germany (I.M.M., V.M.D., A.R., N.L.-A., A.M.V.); and Cancer Research Institute, Arizona State University, Tempe, Arizona (G.R.P.)

Abstract

Cephalostatin 1 is a marine product that induces a novel cytochrome c-independent apoptotic pathway in Jurkat leukemia T cells (Cancer Res 63:8869–8876, 2003). Here, we show that overexpression of the antiapoptotic protein Bcl-2 protects cells only partially against cephalostatin 1-induced apoptosis. The mechanism of Bcl-2 inactivation by cephalostatin 1 is based on hyperphosphorylation of Bcl-2 on Thr69 and Ser87 because Jurkat cells overexpressing a Bcl-2 protein with mutations on both phosphorylation sites were completely protected against cephalostatin 1. In search of the kinase responsible for Bcl-2 phosphorylation, c-Jun NH2-terminal kinase (JNK) was found to be activated by cephalostatin 1. Reduction of Bcl-2 phosphorylation by the specific JNK inhibitor (anthra(1,3-cd)pyrazol-6(2H)-one) SP600125 suggested a crucial role for JNK in this process. JNK activation was not a consequence of DNA damage, a known stimulus of JNK, because cephalostatin 1 did not induce DNA lesions as shown by the comet assay. Arrest in M-phase is also demonstrated to be associated with JNK activation. However, cephalostatin 1 does not evoke an arrest in M-phase as shown by flow cytometry. Together, cephalostatin 1 is shown to induce JNK activation with subsequent Bcl-2 phosphorylation and inactivation. Reported triggers, such as the induction of an M-phase arrest or DNA damage are not involved in this process, suggesting a novel mechanism for cephalostatin 1-mediated Bcl-2 hyperphosphorylation.

Received June 25, 2004; accepted February 8, 2005

Address correspondence to: Dr. Verena M. Dirsch, Department of Pharmacy, Center of Drug Research, University of Munich, Butenandtstra{beta}e 5-13, D-81377 Munich, Germany. E-mail: verena.dirsch{at}cup.uni-muenchen.de






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