Phosphorylation of the Proapoptotic BH3-Only Protein Bid Primes Mitochondria for Apoptosis during Mitotic Arrest

• Published in: Cell reports (Cambridge) 2014-05, Vol.7 (3), p.661-671
• Main Authors: Wang, Pengbo, Lindsay, Jennefer, Owens, Thomas W., Mularczyk, Ewa J., Warwood, Stacey, Foster, Fiona, Streuli, Charles H., Brennan, Keith, Gilmore, Andrew P.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein - antagonists & inhibitors; BH3 Interacting Domain Death Agonist Protein - chemistry; BH3 Interacting Domain Death Agonist Protein - metabolism; Cell Cycle Checkpoints; Cell Line; HEK293 Cells; Humans; Mice; Mitochondria - metabolism; Mitosis; Molecular Sequence Data; Paclitaxel - pharmacology; Phosphopeptides - analysis; Phosphorylation; RNA, Small Interfering - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.03.050

Mitosis is a moment of exquisite vulnerability for a metazoan cell. Failure to complete mitosis accurately can lead to aneuploidy and cancer initiation. Therefore, if the exit from mitosis is delayed, normal cells are usually removed by apoptosis. However, how failure to complete mitosis activates apoptosis is still unclear. Here, we demonstrate that a phosphorylated form of the BH3-only protein Bid regulates apoptosis if mitotic exit is delayed. Bid is phosphorylated on serine 66 as cells enter mitosis, and this phosphorylation is lost during the metaphase-to-anaphase transition. Cells expressing a nonphosphorylatable version of Bid or a BH3-domain mutant were resistant to mitotic-arrest-induced apoptosis. Thus, we show that Bid phosphorylation primes cells to undergo mitochondrial apoptosis if mitotic exit is delayed. Avoidance of this mechanism may explain the selective pressure for cancer cells to undergo mitotic slippage. [Display omitted] •Cell death in mitosis requires the BH3-only protein Bid•Bid becomes phosphorylated on serine 66 as cells enter mitosis•Bid phosphorylation makes mitotic cells dependent on antiapoptotic proteins•Paclitaxel-insensitive cells can be sensitized by targeting this Bcl-2 checkpoint If normal cells don’t align their chromosomes correctly during mitosis, they die. Antimitotic chemotherapy exploits this to kill rapidly dividing cancer cells, but how mitotic arrest activates apoptosis is poorly understood. Wang et al. now show that, whenever a cell enters mitosis, a proapoptotic protein, Bid, becomes phosphorylated, increasing its proapoptotic activity. Once cells are ready to exit mitosis, Bid phosphorylation is lost and the cell is safe. Thus, cells set themselves up to die in case their exit from mitosis is delayed.