The cell cycle is an ordered
sequence of events in which cells grow and divide into two identical daughter
cells. Progression through the cell cycle is mediated by a network of
transcription factors whose activity and expression are regulated via phosphorylation
by cyclin-dependent kinases (Cdks) (Ubersax et al., 2003; Holt et all, 2009;
Landry et al.; 2014). These layers of regulation ensure that cell cycle events
occur at the proper time and only when conditions are favorable for growth.
Therefore, it is not surprising that this transcriptional network is
drastically rewired in response to various environmental stresses.
For example, recent work has
shown that the calcium/calmodulin-dependent kinase calcineurin limits
proliferation by inactivating the S-phase transcription factor, Hcm1, in
response to cellular stress (Arsenault et al., 2015). This led to repression of
Hcm1 target genes and cell cycle arrest (Arsenault et al., 2015).
Interestingly, calcineurin has also been shown to repress gene expression at
every stage of the cell cycle suggesting that it plays a more global role in
regulating stress (unpublished data).
Calcineurin is activated
following the influx of Ca2+ that accompanies cell wall damage,
alkaline pH, and cation imbalance (Nakamura et al., 1993; Viladevall et al., 2004;
Cyert and Philpott, 2013). It seemed plausible that the influx of calcium ions may
also activate another stress pathway. Consistent with this, the Hog1
mitogen-activated protein kinase (MAPK), is activated in response to treatment
with CaCl2 and maintenance of Hog1 activity is dependent on CN
(unpublished data). The HOG pathway
responds to cellular hyper-osmolarity by phosphorylating and activating the
MAPK Hog1 (Saito and Posas, 2003; Brewster et al., 1993; Maeda et al., 1994). To
re-establish osmotic homeostasis, the HOG pathway represses genes important for
the G1/S transition and induces cell cycle arrest (Bellí
et al., 2001). Taken together, these findings suggest that there may be novel
cross-talk between the two stress pathways.