Dissociation of Bax from a Bcl-2/Bax Heterodimer Triggered by Phosphorylation of Serine 70 of Bcl-2.

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Serine 70 in the loop region of Bc1-2 is specifically phosphorylated by paclitaxel-treat-ment in tumor cells and BHK cells expressing Bc1-2. The phosphorylation of serine 70 of Bcl-2 (pS70-Bc1-2) peaks 24 to 48 h after paclitaxel treatment and accelerates apoptosis. Phosphorylation is effectively inhibited in the presence of actinomycin D or cycloheximide, which restore cell viability to the same level as control cells not expressing Bel-2. These results indicate that paclitaxel-induced kinase(s) and/or its activator(s) are syn-thesiz ed novo and play an important role in paclitaxel-induced apoptosis by phospho-rylating Bel-2. In binding assays using the phosphorylation-specific antibody against pS70-Bel-2, the induction of serine 70 phosphorylation 70 results in a loss of the binding ability of Bel-2 to Bax, a pro-apoptotic partner, and induces subsequent cell death. When the pS70-Bel-2 antibody was added to human breast cancer tissue, serine 70 phosphorylation was also detected, even prior to treatment with anticancer agents. Further study of breast cancers revealed 83% of tumors with high pS70-Bc1-2 expression responded to paclitaxel or docetaxel treatment, whereas 57% of those with low expression not respond. These findings suggest that pS70-Bel-2 might be a predictive factor for prognosis and sensitivity to paclitaxel treatment for breast cancer.

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