Mitogen-activated protein kinases (MAPKs) play vital roles in multiple cellular processes and represent prominently pursued targets for development of therapeutic regimes. The MAPK Spc1 (p38 homologue) is known to be very important for both mitotic promotion and delay in Schizosaccharomyces pombe. However, the mechanism responsible for mitotic inhibition has remained elusive. Cdc25 (Cdc2 activator) and Wee1 (Cdc2 inhibtor) are important determinants of mitotic timing in all eukaryotes. Our results show that Spc1 can sense the perturbations in the balance of Cdc25 and Wee1 activities in S. pombe and that its function as a mitotic inhibitor is very important for controlling the same. An Spc1-Srk1-Rad24-dependent pathway for mitotic inhibition has been reported earlier.Here we report the presence of an alternative mechanism wherein Spc1 targets the 14-3-3 protein, Rad24, independently of Srk1, leading to relocalization of Cdc25 and mitotic inhibition. Our observations suggest that this pathway can serve as a backup mechanism for Cdc2 inactivation in the absence of Wee1.

Checkpoint activation and gene expression modulation represent key determinants of cellular survival in adverse conditions. The former is regulated by cyclin-dependent kinases (CDKs) while the latter can be controlled by mitogen-activated protein kinases (MAPKs). Association between cell-cycle progression and MAPK-dependent gene expression exists in cells growing in optimal environments. While MAPK-mediated regulation of the cell cycle is well characterised, the reciprocal influence of mitotic CDK on stress response is not well studied. We present evidence that CDK activity can regulate the extent of MAPK activation in Schizosaccharomyces pombe cells. We show that increasing or decreasing mitotic CDK (Cdc2) activity in S. pombe cells can affect the activation of stress responsive MAPK (Spc1) even in the absence of stress stimuli. Our results indicate that the strong correlation between Cdc2 activity and Spc1 MAPK-activity in S. pombe is important in regulating mitotic timing. This article has an associated First Person interview with the first author of the paper.

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The bZIP transcription factor Atf1 is a key player in the transcriptional programme of Schizosaccharomyces pombe cell cycle. It also controls both expression and degradation of mitotic cyclin Cdc13. Temporal regulation of these opposing functions of Atf1 is critical for fidelity of cell division. Our investigations revealed that an increase in the activity of mitogen-activated protein kinase (MAPK) Spc1 during mitotic exit and the consequent phosphorylation of Atf1 along with the prevailing high activity of cyclin-dependent kinase Cdc2 regulate Cdc13 degradation. Our results also indicate the possibility of a complex interplay between Cdc2 inhibitory kinase Wee1, the anaphase-promoting complex and Atf1 during mitotic exit. These observations provide evidence of new regulatory mechanisms of mitotic exit.

Stress response and checkpoint activation are the main determinants of cellular survival in adverse conditions. In Schizosaccharomyces pombe, these are controlled by the Mitogen Activated Protein Kinase Spc1 and the Cyclin dependent Kinase Cdc2 respectively. Cdc2 is regulated positively by Cdc25 and negatively by Wee1. Changes in Cdc2 activity can be sensed by Spc1 resulting in the modulation of mitotic timing by Spc1. Functional cross talks between cell cycle regulation and MAPK machinery during regulation of mitotic timing are well characterised but the presence of similar communication during stress response remains unexplored. In this study we report how the checkpoint activator kinase Wee1 can also influence the transcriptional response to oxidative stress. We show that deletion of Wee1 results in changes in gene expression of the cells, especially with respect to genes whose expression is known to be regulated by Spc1. These differences are seen in unperturbed cells as well as during oxidative stress. Moreover, such variations extend beyond what could be expected to occur due to the known enhanced Spc1 activity of these cells. This is the first depiction of the influence of Wee1 and consequently Cdc2 activity on transcriptional response to oxidative stress.