RT Journal Article
SR Electronic
T1 Cephalostatin 1 Inactivates Bcl-2 by Hyperphosphorylation Independent of M-Phase Arrest and DNA Damage
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1684
OP 1689
DO 10.1124/mol.104.004234
VO 67
IS 5
A1 Irina M. Müller
A1 Verena M. Dirsch
A1 Anita Rudy
A1 Nancy López-Antón
A1 George R. Pettit
A1 Angelika M. Vollmar
YR 2005
UL http://molpharm.aspetjournals.org/content/67/5/1684.abstract
AB 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.