TY - JOUR
T1 - Cephalostatin 1 inactivates Bcl-2 by hyperphosphorylation independent of M-phase arrest and DNA damage
AU - Müller, Irina M.
AU - Dirsch, Verena M.
AU - Rudy, Anita
AU - López-Antón, Nancy
AU - Pettit, George
AU - Vollmar, Angelika M.
PY - 2005/5
Y1 - 2005/5
N2 - 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 NH 2-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.
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 NH 2-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.
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U2 - 10.1124/mol.104.004234
DO - 10.1124/mol.104.004234
M3 - Article
C2 - 15703383
AN - SCOPUS:17844364586
SN - 0026-895X
VL - 67
SP - 1684
EP - 1689
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -