Abstract
Upon exposure to environmental stressors, cells transiently arrest the cell cycle while they adapt and restore homeostasis. A challenge for all cells is to distinguish between stress signals and coordinate the appropriate adaptive response with cell cycle arrest. Here we investigate the role of the phosphatase calcineurin (CN) in the stress response and demonstrate that CN activates the Hog1/p38 pathway in both yeast and human cells. In yeast, the MAPK Hog1 is transiently activated in response to several well-studied osmostressors. We show that when a stressor simultaneously activates CN and Hog1, CN disrupts Hog1-stimulated negative feedback to prolong Hog1 activation and the period of cell cycle arrest. Regulation of Hog1 by CN also contributes to inactivation of multiple cell cycle-regulatory transcription factors (TFs) and the decreased expression of cell cycle-regulated genes. CN-dependent downregulation of G1/S genes is dependent upon Hog1 activation, whereas CN inactivates G2/M TFs through a combination of Hog1-dependent and -independent mechanisms. These findings demonstrate that CN and Hog1 act in a coordinated manner to inhibit multiple nodes of the cell cycle-regulatory network. Our results suggest that crosstalk between CN and stress-activated MAPKs helps cells tailor their adaptive responses to specific stressors.
Highlights
Cells must constantly monitor their environment and correctly interpret extracellular signals such that they grow and divide only in favorable conditions
This study investigates the role of the phosphatase calcineurin in the stress response and shows that calcineurin inhibits the cell cycle in part by stimulating the activity of the Hog1/p-38 stress-activated MAPK
We show that CN blocks expression of G1/S genes by prolonging the activity of the stress-activated MAPK Hog1, an established inhibitor of G1/S transcription factors (TFs) [13,14]
Summary
Cells must constantly monitor their environment and correctly interpret extracellular signals such that they grow and divide only in favorable conditions. Cells must detect and distinguish among a wide array of environmental stressors including oxidative stress, temperature, DNA damage, and changes in pH or osmolarity. In each of these cases, cells transiently arrest the cell cycle, while promoting stress-specific changes in post-translational modifications and gene expression that allow cells to adapt to their new environment [1]. The mechanisms by which different stress-response pathways work together to coordinate cell cycle arrest and adaptation to specific stressors is not well understood
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