Mitogen-Activated Protein Kinase Hog1 Mediates Adaptation to G₁Checkpoint Arrest during Arsenite and Hyperosmotic Stress

Abstract

Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G 1 and G 2 checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1⌬ mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1⌬ cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G 1 and G 2 delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G 1 cell cycle arrest. Elevated levels of intracellular arsenite and "cross talk" between the HOG and pheromone response pathways, observed in arsenite-treated hog1⌬ cells, prolonged the G 1 delay but did not cause a persistent G 1 arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G 1 exit in hog1⌬ cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1⌬ cells. Interestingly, Sic1-dependent persistent G 1 arrest was also observed in hog1⌬ cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G 1 cell cycle arrest.

The Hog1 MAP Kinase Promotes the Recovery from Cell Cycle Arrest Induced by Hydrogen Peroxide in Candida albicans

“…Hog1, the canonical MAPK of the HOG pathway, has been shown to be involved in G1 progression (Belli et al, 2001). This conclusion is in agreement with a prolonged G1 arrest observed in hog1 mutants after osmotic challenge (Migdal et al, 2008). Hog1 phosphorylates the CDK inhibitor Sic1, reducing the expression of the CLN1 and CLN2 cyclins and, consequently preventing cell cycle progression upon osmotic challenge (Escoté et al, 2004).…”

“…Hog1 has also an important role in G2 phase through stabilization of Swe1, a protein kinase which needs to be degraded for cell cycle progression to occur (Clotet et al, 2006). In addition to osmotic stress, exposure to arsenite also leads to a Hog1-dependent G1 and G2 delay (Migdal et al, 2008). …”

Design, Synthesis, and Characterization of a Highly Effective Hog1 Inhibitor: A Powerful Tool for Analyzing MAP Kinase Signaling in Yeast

“…Thus, by using the HOG1 deletion mutant ( hog1 Δ) only, we could not pin-point neither time nor mechanism of Hog1 action during G 1 cell cycle delay and recovery. Nevertheless, we showed with an analogue-sensitive mutant of Hog1 (Hog1-as) and 1-NM-PP1 inhibitor, that lack of Hog1 kinase activity is responsible for persistent G 1 arrest in the presence of As(III) [20]. However, the results of the cell cycle experiments with the Hog1-as allele were confounded by the fact that in the absence of 1-NM-PP1, the Hog1-as strain displayed much longer As(III)-induced G 1 delay than wild-type cells [14], [20].…”

Oxidative Stress and Replication-Independent DNA Breakage Induced by Arsenic in Saccharomyces cerevisiae

“…It has been reported that As(III) delays the budding yeast cell cycle in all phases [16] and induces phosphorylation of the Rad53 checkpoint kinase (CHK2 in humans) [17]. Importantly, several genome-wide screens have revealed that deletion of yeast genes encoding proteins involved in sensing and repairing of DNA damage, e.g.…”