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Unwinding the loop of Bcl-2 phosphorylation

Abstract

Recent evidence indicates that anti-apoptotic functions of Bcl-2 can be regulated by its phosphorylation. According to the ‘mitotic arrest-induced’ model, multi-site phosphorylation of the Bcl-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of Bcl-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellular contexts. During mitotic arrest, signal transduction is unique and is fundamentally different from classical mitogenic signaling, since the nucleus membrane is dissolved, gene expression is reduced, and numerous kinases and regulatory proteins are hyperphosphorylated. Hyperphosphorylation of Bcl-2 mediated by paclitaxel and other microtubule-active drugs is strictly dependent on targeting microtubules that in turn cause mitotic arrest. In addition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating Bcl-2. A major obstacle for identification of the mitotic Bcl-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotides, pharmacological agents) may arrest cycle, preventing mitosis and Bcl-2 phosphorylation. The role of Bcl-2 phosphorylation in cell death is discussed.

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I thank the section editor James McCubrey and anonymous reviewers for helpful suggestions in editing the manuscript.

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Blagosklonny, M. Unwinding the loop of Bcl-2 phosphorylation. Leukemia 15, 869–874 (2001). https://doi.org/10.1038/sj.leu.2402134

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