Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Fungi | Genetics and Genomics | Molecular Biology
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.
Cell cycle and cell division, Gene expression, Cellular stress responses, Phosphorylation, Cell cycle inhibitors, Synthesis phase, Gene regulation, Cellular crosstalk
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Copyright: © 2020 Leech et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Leech CM, Flynn MJ, Arsenault HE, Ou J, Liu H, Zhu LJ, Benanti JA. The coordinate actions of calcineurin and Hog1 mediate the stress response through multiple nodes of the cell cycle network. PLoS Genet. 2020 Apr 28;16(4):e1008600. doi: 10.1371/journal.pgen.1008600. PMID: 32343701; PMCID: PMC7209309. Link to article on publisher's site
Leech CM, Flynn MJ, Arsenault HE, Ou J, Liu H, Zhu LJ, Benanti JA. (2020). The coordinate actions of calcineurin and Hog1 mediate the stress response through multiple nodes of the cell cycle network. Open Access Articles. https://doi.org/10.1371/journal.pgen.1008600. Retrieved from https://escholarship.umassmed.edu/oapubs/4226
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