Unwinding the loop of Bcl-2 phosphorylation.
Recent evidence indicates that anti-apoptotic functions of BcI-2 can be regulated by its phosphorylation. According to the 'mitotic arrest-induced' model, multi-site phosphorylation of the BcI-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of BcI-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 BcI-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 BcI-2. A major obstacle for identification of the mitotic BcI-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 BcI-2 phosphorylation. The role of BcI-2 phosphorylation in cell death is discussed.
Blagosklonny
M V
MV
Medicine Branch, Building 10, R 12N226, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D007377:Interleukin-3; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011494:Protein Kinases; D017239:Paclitaxel