Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints |
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Authors: | Wang Jianfang Beauchemin Myriam Bertrand Richard |
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Institution: | aCentre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM), Hôpital Notre-Dame and Institut du cancer de Montréal, Montréal, Québec, Canada;bDépartement de médecine, Université de Montréal, Montréal, Québec, Canada |
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Abstract: | Functional analysis of a Bcl-xL phosphorylation mutant series has revealed that cells expressing Bcl-xL(Ser49Ala) mutant are less stable at G2 checkpoint after DNA damage and enter cytokinesis more slowly after microtubule poisoning, than cells expressing wild-type Bcl-xL. These effects of Bcl-xL(Ser49Ala) mutant seem to be separable from Bcl-xL function in apoptosis. Bcl-xL(Ser49) phosphorylation is cell cycle-dependent. In synchronized cells, phospho-Bcl-xL(Ser49) appears during the S phase and G2, whereas it disappears rapidly in early mitosis during prometaphase, metaphase and early anaphase, and re-appears during telophase and cytokinesis. During DNA damage-induced G2 arrest, an important pool of phospho-Bcl-xL(Ser49) accumulates in centrosomes which act as essential decision centers for progression from G2 to mitosis. During telophase/cytokinesis, phospho-Bcl-xL(Ser49) is found with dynein motor protein. In a series of in vitro kinase assays, specific small interfering RNA and pharmacological inhibition experiments, polo kinase 3 (PLK3) was implicated in Bcl-xL(Ser49) phosphorylation. These data indicate that, during G2 checkpoint, phospho-Bcl-xL(Ser49) is another downstream target of PLK3, acting to stabilize G2 arrest. Bcl-xL phosphorylation at Ser49 also correlates with essential PLK3 activity and function, enabling cytokinesis and mitotic exit. |
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Keywords: | Abbreviations: Bcl B cell leukemia/lymphoma protein Bcl-xL Bcl-2-related gene x long isoform BH Bcl-2 homology domain CDC cell division cycle CDK cyclin dependent kinase CLIP170 cytoplasmic linker protein 170 HA influenza hemagglutinin epitope tag PCR polymerase chain reaction PI propidium iodide PLK polo kinase siRNA small interfering RNA VP16 etoposide wt wild-type |
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