Fig 2: p38a Promotes Apoptosis following Chromosome Missegregation(A) Immunoblot showing p38a loss following CRISPR/Cas9-mediated mutation of MAPK14.(B) Immunoblots of parental and p38a null cells exposed to H2O2 for 30 min (left) or AZ3146 for 24 hr (right). Arrow highlights a background band.(C–E) Line graphs (C), cell fate profiles (D), and colony formation assay (E) showing suppression of AZ3146-induced apoptosis in p38a null cells. In (C), values show mean ± SD from three technical replicates and are representative of three independent experiments. Quantitation in (E) shows the mean ± SD derived from two independent experiments.See also Figure S3.

Fig 3: SB203580 Suppresses Apoptosis following Chromosome Missegregation(A) Immunoblots showing p53 loss following CRISPR/Cas9-mediated mutation of TP53.(B and C) Line graphs (B) and cell fate profiles (C) showing that p53 mutation and exposure to the p38 inhibitor SB203580 suppress apoptosis induced by the Mps1 inhibitor AZ3146. In (B), values show mean ± SD from three technical replicates and are representative of three independent experiments. In (C), numbers in bars indicate the percentage of cells exhibiting the fate indicated by bar color.See also Figure S1.

Fig 4: Pharmacological Inhibition of p38 Facilitates Expansion of Aneuploid Clones(A) Experimental design generating clones in the presence or absence of the p38 inhibitor SB203580 following exposure to AZ3146.(B) Chromosome counts showing the deviation from the modal number of 45, analyzing 25 spreads from at least 10 independent clones for each condition.(C) Box and whisker plot showing the average deviation from 45 for clones exposed to AZ3146 ± SB203580. **p < 0.01.(D) Representative M-FISH karyotypes from clones 5A and 5C, both generated in the continuous presence of SB203580. Boxes highlight whole-chromosome aneuploidies.(E) Quantitation of M-FISH karyotypes showing recurrent trisomies for chromosome 2, 9, and 19 (clone 5A) and chromosome 18 (clone 5C).See also Figure S7.

Fig 5: p38 Is Activated following Induction of Whole-Chromosome Aneuploidy(A) Time-lapse image sequences of HCT116 cells expressing GFP-H2B exposed to the Cenp-E inhibitor GSK923295 then AZ3146 to induce missegregation of polar chromosomes. Numbers represent minutes after imaging started; AZ3146 was added at t = 9 min. Scale bar, 10 µm.(B) Canonical p38 MAPK pathway showing upstream regulators and downstream targets.(C) Immunoblots of post-mitotic cells harvested at the time points indicated following exposure to GSK923295 then AZ3146.See also Figure S2.