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Cell Cycle. 2014;13(8):1313-26. doi: 10.4161/cc.28293. Epub 2014 Mar 3.

Phospho-Bcl-xL(Ser62) influences spindle assembly and chromosome segregation during mitosis.

Author information

1
Centre de recherche; Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du Cancer de Montréal; Montréal, Québec, Canada.
2
Centre de recherche; Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du Cancer de Montréal; Montréal, Québec, Canada; Département de médecine; Université de Montréal; Montréal, Québec, Canada.

Abstract

Functional analysis of a series of phosphorylation mutants reveals that Bcl-xL(Ser62Ala) influences cell entry into anaphase and mitotic exit in taxol-exposed cells compared with cells expressing wild-type Bcl-xL or a series of other phosphorylation mutants, an effect that appears to be independent of its anti-apoptotic activity. During normal mitosis progression, Bcl-xL(Ser62) is strongly phosphorylated by PLK1 and MAPK14/SAPKp38α at the prometaphase, metaphase, and the anaphase boundaries, while it is de-phosphorylated at telophase and cytokinesis. Phospho-Bcl-xL(Ser62) localizes in centrosomes with γ-tubulin and in the mitotic cytosol with some spindle-assembly checkpoint signaling components, including PLK1, BubR1, and Mad2. In taxol- and nocodazole-exposed cells, phospho-Bcl-xL(Ser62) also binds to Cdc20- Mad2-, BubR1-, and Bub3-bound complexes, while Bcl-xL(Ser62Ala) does not. Silencing Bcl-xL expression and expressing the phosphorylation mutant Bcl-xL(Ser62Ala) lead to an increased number of cells harboring mitotic spindle defects including multipolar spindle, chromosome lagging and bridging, aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h. Together, the data indicate that during mitosis, Bcl-xL(Ser62) phosphorylation impacts on spindle assembly and chromosome segregation, influencing chromosome stability. Observations of mitotic cells harboring aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h were also made with cells expressing the phosphorylation mutant Bcl-xL(Ser49Ala) and dual mutant Bcl-xL(Ser49/62Ala).

KEYWORDS:

Bcl-xL; MAPK14/SAPKp38α; PLK1; chromosome instability; chromosome segregation; mitosis; spindle-assembly checkpoint

PMID:
24621501
PMCID:
PMC4014433
DOI:
10.4161/cc.28293
[Indexed for MEDLINE]
Free PMC Article

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