Dissociation of Bax from a Bcl-2/Bax heterodimer triggered by phosphorylation of serine 70 of Bcl-2

Serine 70 in the loop region of Bcl-2 is specifically phosphorylated by pac litaxel-treatment in tumor cells and BHK cells expressing Bcl-2. The phosph orylation of serine 70 of Bcl-2 (pS70-Bcl-2) peaks 24 to 48 h after paclita xel treatment and accelerates apoptosis. Phosphorylation is effectively inh ibited in the presence of actinomycin D or cycloheximide, which restore cel l viability to the same level as control cells not expressing Bcl-2. These results indicate that paclitaxel-induced kinase(s) and/or its activator(s) are synthesized de novo and play an important role in paclitaxel-induced ap optosis by phosphorylating Bcl-2. In binding assays using the phosphorylati on-specific antibody against pS70-Bcl-2, the induction of serine 70 phospho rylation 70 results in a loss of the binding ability of Bcl-2 to Bax, a pro -apoptotic partner, and induces subsequent cell death. When the pS70-Bcl-2 antibody was added to human breast cancer tissue, serine 70 phosphorylation was also detected, even prior to treatment with anticancer agents. F-Lu-th er study of breast cancers revealed 83% of tumors with high pS70-Bcl-2 expr ession responded to paclitaxel or docetaxel treatment, whereas 57% of those with low expression not respond. These findings suggest that pS70-Bcl-2 mi ght be a predictive factor for prognosis and sensitivity to paclitaxel trea tment for breast cancer.