Unwinding the loop of Bcl-2 phosphorylation

Recent evidence indicates that anti-apoptotic functions of Bcl-2 can be reg ulated by its phosphorylation. According to the 'mitotic arrest-induced' mo del, multi-site phosphorylation of the Bcl-2 loop domain is followed by cel l death. In contrast, in cytokine-dependent cell lines, cytokines mediate p hosphorylation of Bcl-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellu lar contexts. During mitotic arrest, signal transduction is unique and is f undamentally different from classical mitogenic signaling, since the nucleu s membrane is dissolved, gene expression is reduced, and numerous kinases a nd regulatory proteins are hyperphosphorylated. Hyperphosphorylation of Bcl -2 mediated by paclitaxel and other microtubule-active drugs is strictly de pendent on targeting microtubules that in turn cause mitotic arrest. In add ition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating Bcl-2. A major obstacle for id entification of the mitotic Bcl-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotid es, pharmacological agents) may arrest cycle, preventing mitosis and Bcl-2 phosphorylation. The role of Bcl-2 phosphorylation in cell death is discuss ed.